CA2628283C - Bi-aryl meta-pyrimidine inhibitors of kinases - Google Patents
Bi-aryl meta-pyrimidine inhibitors of kinases Download PDFInfo
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- CA2628283C CA2628283C CA2628283A CA2628283A CA2628283C CA 2628283 C CA2628283 C CA 2628283C CA 2628283 A CA2628283 A CA 2628283A CA 2628283 A CA2628283 A CA 2628283A CA 2628283 C CA2628283 C CA 2628283C
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Abstract
The invention provides biaryl meta-pyrimidine compounds having the general structure (A). The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Jak kinase family, and various other specific receptor and non receptor kinases.
Description
2 BI-ARYL META-PYRIMIDINE INHIBITORS OF KINASES
FIELD OF INVENTION
[0001] The present invention relates to the field of inhibitors of protein tyrosine kinases, their pharmaceutically acceptable compositions comprising the compounds of the invention and the methods of using the compositions in the treatment of various disorders. In particular, the present invention relates to inhibitors of the JAK family of protein tyrosine kinases.
BACKGROUND OF INVENTION
[0002] Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases.
Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited too cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinnse activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility implicated in the aforementioned and related diseases.
FIELD OF INVENTION
[0001] The present invention relates to the field of inhibitors of protein tyrosine kinases, their pharmaceutically acceptable compositions comprising the compounds of the invention and the methods of using the compositions in the treatment of various disorders. In particular, the present invention relates to inhibitors of the JAK family of protein tyrosine kinases.
BACKGROUND OF INVENTION
[0002] Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases.
Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited too cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinnse activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation, survival, apoptosis, mitogenesis, cell cycle control, and cell mobility implicated in the aforementioned and related diseases.
[0003] Protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (Jakl, Jak2, Jak3, and Tyk2) play a central role in cytokine signaling (Kisseleva et al, Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-ccs/P/o/Limitin, IFN-7, IL-10, IL-19, IL-20, IL-22), the gp130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin, IL-12, IL-23), 'yC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (1L-3, 1L-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and 0-protein coupled receptors (AT1).
[0004] Until recently, the therapeutic potential of JAK inhibitors has focused on diseases affecting various pathologies of the immune system. These include, but are not limited to atopy (allergic asthma, atopic dermatitis, allergic rhinitis), cell mediated hypersensitivity (allergic contact delinatitis, hypersensitivity pneumonitis), rheumatic diseases (systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), transplantation (transplant rejection, graft vs host disease), viral diseases (Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, HTLV1, Vaicella-Zoster Virus, Human Papilloma Virus), cancer (leukemia, lymphoma), cardiovascular disease (cardiac hypertrophy, atherosclerosis and arteriosclerosis), neurodegenerative diseases (motor neuron disease), food allergy, inflammatory bowel disease, Crohn's disease, cutaneous inflammation, and immune suppression induced by solid tumors. Most efforts to date have targeted JAK3 inhibition for immunosuppression, for example organ transplantation and allograft acceptance (for a review, see Boric et al. Current Opinion in Investigational Drugs, 2003, 4(11), 1297).
[0005] Most recently, two significant findings of the role of the EPO-JAK2 signaling pathway in myeloproliferative disorders and prolfierative diabetic retinopathy were found.
First, a gain-of-function, somatic (acquired) mutation of the JAK2 kinase (V617F) was reported to be a causative factor in a number of "typical" myeloproliferative disorders, including polycethemia vera, essential thrombocythemia and melofibrosis with myeloid metaplasia, and the mutation has been found in patients with either "atypical"
myeloproliferative disorders and myelodysplastic syndrome (for reviews see Tefferi and Gilliland, Cell Cycle 2005, 4(8), e61; Pesu et. al. Molecular Interventions 2005, 5(4), 211).
Additionally it was found that (a) the V617F JAK2 mutation was associated with constitutive phosphorylation of JAK2 and its downstream effectors as well as induction of erythropoietin hypersensitivity in cell based experiments, (b) V617F JAM-indcued cell proliferation signals were inhibited by small molecule inhibitors of JAK2, and (c) murine bone marrow transduced with a retrovirus containing V617F JAK2 incuded erythrocytosis in the transplanted mice.
First, a gain-of-function, somatic (acquired) mutation of the JAK2 kinase (V617F) was reported to be a causative factor in a number of "typical" myeloproliferative disorders, including polycethemia vera, essential thrombocythemia and melofibrosis with myeloid metaplasia, and the mutation has been found in patients with either "atypical"
myeloproliferative disorders and myelodysplastic syndrome (for reviews see Tefferi and Gilliland, Cell Cycle 2005, 4(8), e61; Pesu et. al. Molecular Interventions 2005, 5(4), 211).
Additionally it was found that (a) the V617F JAK2 mutation was associated with constitutive phosphorylation of JAK2 and its downstream effectors as well as induction of erythropoietin hypersensitivity in cell based experiments, (b) V617F JAM-indcued cell proliferation signals were inhibited by small molecule inhibitors of JAK2, and (c) murine bone marrow transduced with a retrovirus containing V617F JAK2 incuded erythrocytosis in the transplanted mice.
[0006] Furthermore, recently it has been found that mutations in EPO-R also keep the JAK pathway constitutively activated leading to myleoproliferative disorders.
[0007] Second, EPO was found to be a potent angiogenic factor in proliferative diabetic retinopathy, a major cause of vision loss affecting diabetic, working-age persons (see for example Aiello, New England Journal of Medicine, 2005, 353 (8), 839; Watanabe et al. New England Journal of Medicine 2005 353 (8), 782).
[0008] Further, findings from the Watanabe research showed (a) intraocular EPO
levels and VEGF (another well-known angiogenic factor in proliferative diabetic retinopathy) were significantly higher among those with proliferative diabetic retinopathy than those with quiescent disease or non-diabetic control, (b) EPO and VEGF levels were not closely correlated, (c) EPO levels were more strongly correlated with the presence of proliferative diabetic retinopathy than VEGF, (d) EPO stimulated growth and intracellular signaling in retinal endothelial cells, and (e) inhibitors of either EPO or VEGF reduced hypoxia-induced retinal neovascularization in rodent models.
levels and VEGF (another well-known angiogenic factor in proliferative diabetic retinopathy) were significantly higher among those with proliferative diabetic retinopathy than those with quiescent disease or non-diabetic control, (b) EPO and VEGF levels were not closely correlated, (c) EPO levels were more strongly correlated with the presence of proliferative diabetic retinopathy than VEGF, (d) EPO stimulated growth and intracellular signaling in retinal endothelial cells, and (e) inhibitors of either EPO or VEGF reduced hypoxia-induced retinal neovascularization in rodent models.
[0009] Recently it has been shown that mutations in the EPO receptor may also affect the signaling related to the JAK pathway and this may have implications in terms of disease states where JAK signaling is important in the cell cycle.
[0010] There is another feature regarding inhibitors of the JAK pathway. It has been demonstrated that the JAK pathway may be recruited in cell survival and proliferation. For example, in the case of the cells that are Philadelphia chromosome positive that result in chronic myelogenous leukemia (CML), there is evidence that the Jak pathway is recruited in constitutive activation. Accordingly, using a JAK inhibitor may have use in CML in which the Philadephia chromosome has been shown to produce the hybrid Bcr-Abl, thus keeping cells constitutively active.
[0011] More telling is that in cases of resistance mutations that arise on account of specific inhibitors to BCR-ABL, as in the case of the T315I gatekeeper mutation, or any other mutation, it may be possible to use a JAK inhibitor on account of the pathway used by the BCR-ABL mutant (as in the case of BCR-ABL(T315I) mutation) utilizing the Jak pathway.
Thus Jak inhibitors may be used in the treatment of patients with resistance to known therapies where BCR-ABL is directly targeted and drug resistance has now been shown as the dominant (50-90%) of all resistance in patients where existing therapies fail.
[00121 The use of JAK inhibitors may also find utility in other myeloid disease states, both blood disorders and other disease states with myeloid implications, and other disease states in which the JAK pathway is implicated directly or indirectly.
100131 Accordingly, there is a need to develop compounds useful as inhibitors of kinases, particularly, JAK kinase, given the inadequate treatments available for the aforementioned diseases where the MK signaling pathway is dysregulated, or recruited directly or indirectly.
SUMMARY
[00141 According to one embodiment, a compound having the structure (A) is provided:
Q
R311, H
N p G0 -127-1 q n .R4 H N N
H H
(A) [00153 According to another embodiment, a method is provided for treating an angiogenie-associated disorder, the method including administering to a subject in need thereof a therapeutically effective amount of at least one compound having the structure (A), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, crystal forms, N-oxides, and individual enatiomers and diastereomers thereof, to a subject in need of such treatment.
[0016] According to other embodiments, pharmaceutical compositions and articles of manufacture are provided, including at least one compound having the structure (A), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE I illustrates data obtained from FACS analysis of circulating tumor burden.
FIGURE 2 illustrates data obtained from an in vivo study using a circulating tumor model.
DETAILED DESCRIPTION
A. Terms and Definitions.
[0017] The following terminology and definitions apply as used in the present application, generally in conformity with the terminology recommended by the International Union of Pure and Applied Chemistry (IUPAC):
[0018] The term "heteroatom" refers to any atom other than carbon, for example, N, 0, or S.
[0019] The term "aromatic" refers to a cyclically conjugated molecular entity with a stability, due to delocalization, significantly greater than that of a hypothetical localized structure, such as the Kekule structure.
[0020] The term "heterocyclic," when used to describe an aromatic ring, refers to the aromatic rings containing at least one heteroatom, as defined above.
[0021] The term "heterocyclic," when not used to describe an aromatic ring, refers to cyclic (i.e., ring-containing) groups other than aromatic groups, the cyclic group being formed by between 3 and about 14 carbon atoms and at least one heteroatom described above.
[0022] The term "substituted heterocyclic" refers, for both aromatic and non-aromatic structures, to heterocyclic groups further bearing one or more substituents described below.
[0023] The term "alkyl" refers to a monovalent straight or branched chain hydrocarbon group having from one to about 12 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl (also known as n-amyl), n-hexyl, and the like.
The term "lower alkyl" refers to alkyl groups having from 1 to about 6 carbon atoms.
[0024] The term "substituted alkyl" refers to alkyl groups further bearing one or more substituents such as hydroxy, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, sulfuryl, and the like.
[0025] The term "alkenyl" refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon double bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkenyl" refers to alkenyl groups further bearing one or more substituents described above.
[00261 The term "alkynyl" refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon triple bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkynyl" refers to alkynyl groups further bearing one or more substituents described above.
[0027] The term "aryl" refers to aromatic groups having between about 5 and about 14 carbon atoms and the term "substituted aryl" refers to aryl groups further bearing one or more substituents described above.
[0028] The term "heteroaryl" refers to aromatic rings, where the ring structure is formed by between 3 and about 14 carbon atoms and by at least one heteroatom described above, and the term "substituted heteroaryl" refers to heteroaryl groups further bearing one or more substituents described above.
[0029] The term "alkoxy" refers to the moiety ¨0¨alkyl, wherein alkyl is as defined above, and the term "substituted alkoxy" refers to alkoxy groups further bearing one or more substituents described above.
[0030] The term "cycloalkyl" refers to alkyl groups having between 3 and about 8 carbon atoms arranged as a ring, and the term "substituted cycloalkyl" refers to cycloalkyl groups further bearing one or more substituents described above.
[0031] The term "alkylaryl" refers to alkyl-substituted aryl groups and the teini "substituted alkylaryl" refers to alkylaryl groups further bearing one or more substituents described above.
[0032] The term "arylalkyl" refers to aryl-substituted alkyl groups and the term "substituted arylalkyl" refers to arylalkyl groups further bearing one or more substituents described above.
[0033] The term "arylalkenyl" refers to aryl-substituted alkenyl groups and the term "substituted arylalkenyl" refers to arylalkenyl groups further bearing one or more substituents described above.
[0034] The term "arylalkynyl" refers to aryl-substituted alkynyl groups and the term "substituted arylalkynyl" refers to arylalkynyl groups further bearing one or more substituents described above.
[0035] The term "arylene" refers to divalent aromatic groups having between 5 and about 14 carbon atoms and the term "substituted arylene" refers to arylene groups further bearing one or more substituents described above.
[0036] The term "chemically connected" is defined as forming a chemical entity in which two moieties form a direct chemical bond between them.
[0037] The term "kinase" refers to any enzyme that catalyzes the addition of phosphate groups to a protein residue; for example, serine and threonine kinases catalyze the addition of phosphate groups to serine and threonine residues.
[0038] The term "JAK kinase" refers to an enzyme found in cells in the immune system that participates in the cell signaling process resulting in the development of white blood cells.
[0039] The term "therapeutically effective amount" refers to the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, e.g., restoration or maintenance of vasculostasis or prevention of the compromise or loss or vasculostasis; reduction of tumor burden; reduction of morbidity and/or mortality.
[0040] The term "pharmaceutically acceptable" refers to the fact that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0041] The terms "administration of a compound" or "administering a compound"
refer to the act of providing a compound of the invention or pharmaceutical composition to the subject in need of treatment.
[0042] The term "antibody" refers to intact molecules of polyclonal or monoclonal antibodies, as well as fragments thereof, such as Fab and F(ab1)2, Fv and SCA
fragments which are capable of binding an epitopic determinant.
[0043] The term "vasculostasis" refers to the maintenance of the homeostatic vascular functioning leading to the normal physiologic functioning.
[0044] The term "vasculostatic agents" refers to agents that seek to address conditions in which vasculostasis is compromised by preventing the loss of or restoring or maintaining vasculostasis.
B. Embodiments of the Invention.
[0045] According to an embodiment of the invention, compounds having the structure (A) are provided for treatment of various diseases, disorders, and pathologies:
Q
N
(,.1 I
____________________________________ X q G .
P n R4 H N
- R1 R2 =
H H
(A) [0046] In the structure (A), X can be any of a bond, 0, C=0, SO2, or CH2 and Y
can be a bond or NR9; or X and Y taken together can be a bond. Further, in the structure (A) each of Rl and R2 can be any of H, C1-C6 substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or RI. and R2 taken together can be a bond; or RI and R2 taken together can form a moiety such as one of (CH2)m, (CH2),--S¨(CH2)m, (CH2),--80¨(CH2)m, (CH2),¨S02¨(CH2)m, (CH2),--NR9¨(CH2)m, or (CH2)i-0¨(CH2)m, wherein each of p, q, r, n, m is idependently an integer having the value between 0 and 6.
[0047] Further, in the structure (A) R9 can be one of H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 branched alkyl, C1-C6 substituted alkyl, C1-C6 aminoalkyl, or C1-C6 hydroxyalkyl; Go can be one of N, 0, H, of CH, with the proviso that if Go is N, then each of R3 and R4 can be one of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C1-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R3 and R4 taken together can form a moiety such as one of (CH2)1¨S¨(CH2)m, (CH2)i¨S0¨(CH2)m, (CH2)r¨S02¨(CH2)m, (CH2),¨NR9¨(CH2)m, or (CH2),-0¨(CH2)m.
[0048] There are some additional provisos further directed to Go in the structure (A).
More specifically, if Go is N, then R1 and R9 taken together can form a moiety such as one of - (CH2)111, (CH2)r¨S¨(CH2)m, (CH2)r¨S0¨(C112)m, CH2),¨S02¨(CH2)m, (CH2),¨NR9¨(CH2)m, or (CH2)r-0¨(CH2)m; or R1 and R4 taken together can form a moiety such as one of (CH2)1, (CH2)r¨S¨(CH2)m, (CH2),--S0¨(CH2)m, (CH2)r¨S02¨(CH2)m, (CH2),¨NR9¨(CH2)m, or (CH2),-0¨(CH2).; or R9 and R4 taken together can form a moiety such as one of (CH2)1,, (CH2)r¨S¨(CH2)m, (CH2)t¨S0¨(CH2)m, (CH2)r-S02¨(042)m, (CH2)r¨NR9¨(CH2)m, or (CH2),-0¨(CH2)m, or R3 and R4 taken together can form a moiety such as one of (CH2)1, (CH2),¨S¨(CH2)m, (CH2)r¨S0¨(CH2)m, (CH2)r¨S02¨(CH2)m, (CH2),¨NR6¨(CH2)m, or (CH2)r-0¨(C112)m.
[0049] If in the structure (A) Go is 0, then R3 can be one of H, C-C6 alkyl and Cl-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cycloalkyl, substituted heterocyclic connected through carbon or nitrogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl connected through carbon or nitrogen, with no group R4; R1 and R9 taken together can form a moiety such as one of (CH2)., (CH2)r¨S¨(CH2)m, (CH2),¨S0¨(CH2)m, (CH2),¨S02¨(CH2)m, (CH2),--NR9¨(CH2)õõ or (CH2),-0¨(CH2)m; or RI and R3 taken together can faun a moiety such as one of (CH2)m, (CH2)r¨S¨(CH2)m, (CH2),¨S0¨(CH2)m, (CH2)1¨S02¨(CH2)m, (CH2),¨NR9¨(CH2)m, or (CH2)r-0¨(CH2)m; or R9 and R3 taken together can form a moiety such as one of (CH2)1, (CH2)1¨S¨(CH2)1,,, (CH2)r¨S0¨(CH2)m, (CH2)r¨
S02¨(CH2)., (CH2),¨NR9¨(CH2)õõ or (CH2),-0¨(CH2)m.
[0050] If in the structure (A) Go = CH, then each of R3 and R4 can be one of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C1-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, C1-C6 substituted or unsubstituted heterocycle connected through carbon or nitrogen, or substituted or unsubstituted heteroaryl connected through carbon or nitrogen, or R3 and R4 taken together can form a moiety such as one of (CHR9)r-(CHR9)1fl-(CHR9)1õ (CHR9)1-S-(CHR9)1, (CHR9)r-S0-(CHR9)m, (CHR9),-SO2-(CHR9)m, (CHR9),-NR9-(CHR9)m, or (CHR9)1-0-(CHR9)..
[0051] Further, in the structure (A) G can be N or CR6, and each G is independent of each other G, with the further proviso that not more than two groups G can be N, with the further proviso that for each CR6, each R6 is independent of each other group R6.
[0052] Further, in the structure (A) R5 is methyl and the moiety Q is as shown below Q=
, %.52 G
[0053] In the moiety Q, each of R6, R7, R8 can be one of H, C1-C6 substituted or unsubstituted alkyl, C1-C6 substituted or unsubstituted alkenyl, C1-C6 substituted or unsubstituted alkynyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, Ci-C6 substituted or unsubstituted branched alkyl, C1-C6 substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl connected through carbon or a heteroatom, substituted or unsubstituted heteroaryl connected through carbon or a heteroatom, C1-C6 alkoxy, a halogen, CF3, -0CF3, CHR3R4, SR3, SOR3, S02R3, SO2NR3R4, S03R3, POR3, P02R3, PO2NR3R4, PO2CR3R4, P03R3, NR3R4, NO2, CN, OH, CONR3R4, COR3, COOR3, N R3C0 R4, NR3CONR3R4, OCONR3R4, CSNR3R4, CSR3, NR3CSNR3R4, SCONR3R4, SCSNR3R4, or SCSNR3R4; or any of R6 and R7 takentogether, or R7 and R8 taken together, or R6 and R8 taken together can form a moeity independently selected from any of -HN-CH=CH-, -HN-N=CH-, -HN-N=N-, -0(CH2)n0-, -S(CH2).S-, -N=CH-S-, -CH=N-0-, -CH=N-S - , -N=CH-O-, -- C-N 0, C-N 0, CH-CH CH-CH--, -N=CH-CH=CH-, ¨CH=N¨CH=CH¨, ¨0¨CH=CH, and ¨S¨CH=CH¨; or R3 and R4 taken together can form a moiety such as one of (CHR9),¨(CHR9),1¨(CHR9)1, (CHR9),¨S¨(CHR9)in, (CHR9)1¨S0¨(CHR9),,, (CHR9),¨S02¨(CHR9) (CHR9)1¨NR9¨(CHR9)1, or (CHR9)1-0¨
(CHR9)m.
[0054] Further, in the structure (A), A can be one of 0, NR3, CR3R4, S, SO, and SO2; and in the moiety Q, Gi can be any of CH, N, NH, S, and 0, and G2 can be any of CR7, N, NH, S, and 0, with each group R7 being independent of every other group R7; and if G1 or G2 is NH, S, or 0, then Q is a five membered heteroaromatic ring, optionally fused to a six member aromatic or non-aromatic ring; and if G1 or G2 is N, then Q is a five or a six membered aromatic ring, optionally fused to a six member aromatic or non-aromatic ring, with the further proviso that X or Go includes at least one heteroatom included with X
and selected from 0, S and N, or Go comprises at least four non-hydrogen atoms, inclusive of the heteroatom, and R3 and R4, or le and R9, or le and R4, or R9 and R4 taken together can form an aromatic, heteroaromatic, cyclic or heterocyclic ring system, or if a noncyclic system is present, then more than one heteroatom is present, and if A is NR3, then any of R.6, R7 or R8, or any combination thereof independently includes at least two non-hydrogen sub stituents, or if A is NR3, then Q fauns a fused ring from R6 to R7, or from R7 to Rg.
[0055] Some exemplary compounds described by structure (A) that can be used include, but are not limited to, the following compounds I through CLXII shown below:
N NO
NN
N N
)`-I H
Thus Jak inhibitors may be used in the treatment of patients with resistance to known therapies where BCR-ABL is directly targeted and drug resistance has now been shown as the dominant (50-90%) of all resistance in patients where existing therapies fail.
[00121 The use of JAK inhibitors may also find utility in other myeloid disease states, both blood disorders and other disease states with myeloid implications, and other disease states in which the JAK pathway is implicated directly or indirectly.
100131 Accordingly, there is a need to develop compounds useful as inhibitors of kinases, particularly, JAK kinase, given the inadequate treatments available for the aforementioned diseases where the MK signaling pathway is dysregulated, or recruited directly or indirectly.
SUMMARY
[00141 According to one embodiment, a compound having the structure (A) is provided:
Q
R311, H
N p G0 -127-1 q n .R4 H N N
H H
(A) [00153 According to another embodiment, a method is provided for treating an angiogenie-associated disorder, the method including administering to a subject in need thereof a therapeutically effective amount of at least one compound having the structure (A), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, crystal forms, N-oxides, and individual enatiomers and diastereomers thereof, to a subject in need of such treatment.
[0016] According to other embodiments, pharmaceutical compositions and articles of manufacture are provided, including at least one compound having the structure (A), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGURE I illustrates data obtained from FACS analysis of circulating tumor burden.
FIGURE 2 illustrates data obtained from an in vivo study using a circulating tumor model.
DETAILED DESCRIPTION
A. Terms and Definitions.
[0017] The following terminology and definitions apply as used in the present application, generally in conformity with the terminology recommended by the International Union of Pure and Applied Chemistry (IUPAC):
[0018] The term "heteroatom" refers to any atom other than carbon, for example, N, 0, or S.
[0019] The term "aromatic" refers to a cyclically conjugated molecular entity with a stability, due to delocalization, significantly greater than that of a hypothetical localized structure, such as the Kekule structure.
[0020] The term "heterocyclic," when used to describe an aromatic ring, refers to the aromatic rings containing at least one heteroatom, as defined above.
[0021] The term "heterocyclic," when not used to describe an aromatic ring, refers to cyclic (i.e., ring-containing) groups other than aromatic groups, the cyclic group being formed by between 3 and about 14 carbon atoms and at least one heteroatom described above.
[0022] The term "substituted heterocyclic" refers, for both aromatic and non-aromatic structures, to heterocyclic groups further bearing one or more substituents described below.
[0023] The term "alkyl" refers to a monovalent straight or branched chain hydrocarbon group having from one to about 12 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl (also known as n-amyl), n-hexyl, and the like.
The term "lower alkyl" refers to alkyl groups having from 1 to about 6 carbon atoms.
[0024] The term "substituted alkyl" refers to alkyl groups further bearing one or more substituents such as hydroxy, alkoxy, mercapto, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, sulfuryl, and the like.
[0025] The term "alkenyl" refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon double bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkenyl" refers to alkenyl groups further bearing one or more substituents described above.
[00261 The term "alkynyl" refers to straight-chained or branched hydrocarbyl groups having at least one carbon-carbon triple bond, and having between about 2 and about 12 carbon atoms, and the term "substituted alkynyl" refers to alkynyl groups further bearing one or more substituents described above.
[0027] The term "aryl" refers to aromatic groups having between about 5 and about 14 carbon atoms and the term "substituted aryl" refers to aryl groups further bearing one or more substituents described above.
[0028] The term "heteroaryl" refers to aromatic rings, where the ring structure is formed by between 3 and about 14 carbon atoms and by at least one heteroatom described above, and the term "substituted heteroaryl" refers to heteroaryl groups further bearing one or more substituents described above.
[0029] The term "alkoxy" refers to the moiety ¨0¨alkyl, wherein alkyl is as defined above, and the term "substituted alkoxy" refers to alkoxy groups further bearing one or more substituents described above.
[0030] The term "cycloalkyl" refers to alkyl groups having between 3 and about 8 carbon atoms arranged as a ring, and the term "substituted cycloalkyl" refers to cycloalkyl groups further bearing one or more substituents described above.
[0031] The term "alkylaryl" refers to alkyl-substituted aryl groups and the teini "substituted alkylaryl" refers to alkylaryl groups further bearing one or more substituents described above.
[0032] The term "arylalkyl" refers to aryl-substituted alkyl groups and the term "substituted arylalkyl" refers to arylalkyl groups further bearing one or more substituents described above.
[0033] The term "arylalkenyl" refers to aryl-substituted alkenyl groups and the term "substituted arylalkenyl" refers to arylalkenyl groups further bearing one or more substituents described above.
[0034] The term "arylalkynyl" refers to aryl-substituted alkynyl groups and the term "substituted arylalkynyl" refers to arylalkynyl groups further bearing one or more substituents described above.
[0035] The term "arylene" refers to divalent aromatic groups having between 5 and about 14 carbon atoms and the term "substituted arylene" refers to arylene groups further bearing one or more substituents described above.
[0036] The term "chemically connected" is defined as forming a chemical entity in which two moieties form a direct chemical bond between them.
[0037] The term "kinase" refers to any enzyme that catalyzes the addition of phosphate groups to a protein residue; for example, serine and threonine kinases catalyze the addition of phosphate groups to serine and threonine residues.
[0038] The term "JAK kinase" refers to an enzyme found in cells in the immune system that participates in the cell signaling process resulting in the development of white blood cells.
[0039] The term "therapeutically effective amount" refers to the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, e.g., restoration or maintenance of vasculostasis or prevention of the compromise or loss or vasculostasis; reduction of tumor burden; reduction of morbidity and/or mortality.
[0040] The term "pharmaceutically acceptable" refers to the fact that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0041] The terms "administration of a compound" or "administering a compound"
refer to the act of providing a compound of the invention or pharmaceutical composition to the subject in need of treatment.
[0042] The term "antibody" refers to intact molecules of polyclonal or monoclonal antibodies, as well as fragments thereof, such as Fab and F(ab1)2, Fv and SCA
fragments which are capable of binding an epitopic determinant.
[0043] The term "vasculostasis" refers to the maintenance of the homeostatic vascular functioning leading to the normal physiologic functioning.
[0044] The term "vasculostatic agents" refers to agents that seek to address conditions in which vasculostasis is compromised by preventing the loss of or restoring or maintaining vasculostasis.
B. Embodiments of the Invention.
[0045] According to an embodiment of the invention, compounds having the structure (A) are provided for treatment of various diseases, disorders, and pathologies:
Q
N
(,.1 I
____________________________________ X q G .
P n R4 H N
- R1 R2 =
H H
(A) [0046] In the structure (A), X can be any of a bond, 0, C=0, SO2, or CH2 and Y
can be a bond or NR9; or X and Y taken together can be a bond. Further, in the structure (A) each of Rl and R2 can be any of H, C1-C6 substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or RI. and R2 taken together can be a bond; or RI and R2 taken together can form a moiety such as one of (CH2)m, (CH2),--S¨(CH2)m, (CH2),--80¨(CH2)m, (CH2),¨S02¨(CH2)m, (CH2),--NR9¨(CH2)m, or (CH2)i-0¨(CH2)m, wherein each of p, q, r, n, m is idependently an integer having the value between 0 and 6.
[0047] Further, in the structure (A) R9 can be one of H, C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 branched alkyl, C1-C6 substituted alkyl, C1-C6 aminoalkyl, or C1-C6 hydroxyalkyl; Go can be one of N, 0, H, of CH, with the proviso that if Go is N, then each of R3 and R4 can be one of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C1-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R3 and R4 taken together can form a moiety such as one of (CH2)1¨S¨(CH2)m, (CH2)i¨S0¨(CH2)m, (CH2)r¨S02¨(CH2)m, (CH2),¨NR9¨(CH2)m, or (CH2),-0¨(CH2)m.
[0048] There are some additional provisos further directed to Go in the structure (A).
More specifically, if Go is N, then R1 and R9 taken together can form a moiety such as one of - (CH2)111, (CH2)r¨S¨(CH2)m, (CH2)r¨S0¨(C112)m, CH2),¨S02¨(CH2)m, (CH2),¨NR9¨(CH2)m, or (CH2)r-0¨(CH2)m; or R1 and R4 taken together can form a moiety such as one of (CH2)1, (CH2)r¨S¨(CH2)m, (CH2),--S0¨(CH2)m, (CH2)r¨S02¨(CH2)m, (CH2),¨NR9¨(CH2)m, or (CH2),-0¨(CH2).; or R9 and R4 taken together can form a moiety such as one of (CH2)1,, (CH2)r¨S¨(CH2)m, (CH2)t¨S0¨(CH2)m, (CH2)r-S02¨(042)m, (CH2)r¨NR9¨(CH2)m, or (CH2),-0¨(CH2)m, or R3 and R4 taken together can form a moiety such as one of (CH2)1, (CH2),¨S¨(CH2)m, (CH2)r¨S0¨(CH2)m, (CH2)r¨S02¨(CH2)m, (CH2),¨NR6¨(CH2)m, or (CH2)r-0¨(C112)m.
[0049] If in the structure (A) Go is 0, then R3 can be one of H, C-C6 alkyl and Cl-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, substituted or unsubstituted branched alkyl, substituted or unsubstituted cycloalkyl, substituted heterocyclic connected through carbon or nitrogen, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl connected through carbon or nitrogen, with no group R4; R1 and R9 taken together can form a moiety such as one of (CH2)., (CH2)r¨S¨(CH2)m, (CH2),¨S0¨(CH2)m, (CH2),¨S02¨(CH2)m, (CH2),--NR9¨(CH2)õõ or (CH2),-0¨(CH2)m; or RI and R3 taken together can faun a moiety such as one of (CH2)m, (CH2)r¨S¨(CH2)m, (CH2),¨S0¨(CH2)m, (CH2)1¨S02¨(CH2)m, (CH2),¨NR9¨(CH2)m, or (CH2)r-0¨(CH2)m; or R9 and R3 taken together can form a moiety such as one of (CH2)1, (CH2)1¨S¨(CH2)1,,, (CH2)r¨S0¨(CH2)m, (CH2)r¨
S02¨(CH2)., (CH2),¨NR9¨(CH2)õõ or (CH2),-0¨(CH2)m.
[0050] If in the structure (A) Go = CH, then each of R3 and R4 can be one of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C1-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted aryl, C1-C6 substituted or unsubstituted heterocycle connected through carbon or nitrogen, or substituted or unsubstituted heteroaryl connected through carbon or nitrogen, or R3 and R4 taken together can form a moiety such as one of (CHR9)r-(CHR9)1fl-(CHR9)1õ (CHR9)1-S-(CHR9)1, (CHR9)r-S0-(CHR9)m, (CHR9),-SO2-(CHR9)m, (CHR9),-NR9-(CHR9)m, or (CHR9)1-0-(CHR9)..
[0051] Further, in the structure (A) G can be N or CR6, and each G is independent of each other G, with the further proviso that not more than two groups G can be N, with the further proviso that for each CR6, each R6 is independent of each other group R6.
[0052] Further, in the structure (A) R5 is methyl and the moiety Q is as shown below Q=
, %.52 G
[0053] In the moiety Q, each of R6, R7, R8 can be one of H, C1-C6 substituted or unsubstituted alkyl, C1-C6 substituted or unsubstituted alkenyl, C1-C6 substituted or unsubstituted alkynyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, Ci-C6 substituted or unsubstituted branched alkyl, C1-C6 substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl connected through carbon or a heteroatom, substituted or unsubstituted heteroaryl connected through carbon or a heteroatom, C1-C6 alkoxy, a halogen, CF3, -0CF3, CHR3R4, SR3, SOR3, S02R3, SO2NR3R4, S03R3, POR3, P02R3, PO2NR3R4, PO2CR3R4, P03R3, NR3R4, NO2, CN, OH, CONR3R4, COR3, COOR3, N R3C0 R4, NR3CONR3R4, OCONR3R4, CSNR3R4, CSR3, NR3CSNR3R4, SCONR3R4, SCSNR3R4, or SCSNR3R4; or any of R6 and R7 takentogether, or R7 and R8 taken together, or R6 and R8 taken together can form a moeity independently selected from any of -HN-CH=CH-, -HN-N=CH-, -HN-N=N-, -0(CH2)n0-, -S(CH2).S-, -N=CH-S-, -CH=N-0-, -CH=N-S - , -N=CH-O-, -- C-N 0, C-N 0, CH-CH CH-CH--, -N=CH-CH=CH-, ¨CH=N¨CH=CH¨, ¨0¨CH=CH, and ¨S¨CH=CH¨; or R3 and R4 taken together can form a moiety such as one of (CHR9),¨(CHR9),1¨(CHR9)1, (CHR9),¨S¨(CHR9)in, (CHR9)1¨S0¨(CHR9),,, (CHR9),¨S02¨(CHR9) (CHR9)1¨NR9¨(CHR9)1, or (CHR9)1-0¨
(CHR9)m.
[0054] Further, in the structure (A), A can be one of 0, NR3, CR3R4, S, SO, and SO2; and in the moiety Q, Gi can be any of CH, N, NH, S, and 0, and G2 can be any of CR7, N, NH, S, and 0, with each group R7 being independent of every other group R7; and if G1 or G2 is NH, S, or 0, then Q is a five membered heteroaromatic ring, optionally fused to a six member aromatic or non-aromatic ring; and if G1 or G2 is N, then Q is a five or a six membered aromatic ring, optionally fused to a six member aromatic or non-aromatic ring, with the further proviso that X or Go includes at least one heteroatom included with X
and selected from 0, S and N, or Go comprises at least four non-hydrogen atoms, inclusive of the heteroatom, and R3 and R4, or le and R9, or le and R4, or R9 and R4 taken together can form an aromatic, heteroaromatic, cyclic or heterocyclic ring system, or if a noncyclic system is present, then more than one heteroatom is present, and if A is NR3, then any of R.6, R7 or R8, or any combination thereof independently includes at least two non-hydrogen sub stituents, or if A is NR3, then Q fauns a fused ring from R6 to R7, or from R7 to Rg.
[0055] Some exemplary compounds described by structure (A) that can be used include, but are not limited to, the following compounds I through CLXII shown below:
N NO
NN
N N
)`-I H
12 HO
NH
s,NN
N
NN
O NH
ti?
N
%1Nr- N
IV
HO NH
N
V
<
O NH
N NO
N
VI
CI
O N
N
NH
s,NN
N
NN
O NH
ti?
N
%1Nr- N
IV
HO NH
N
V
<
O NH
N NO
N
VI
CI
O N
N
13 CI
NH
VIII
CL'-NtD
N
Cl N
N
Ix 1.1 NH
N
N
X
ci NH
N
XI
CI
N
NH
VIII
CL'-NtD
N
Cl N
N
Ix 1.1 NH
N
N
X
ci NH
N
XI
CI
N
14 NH
NN
XIII
NH
N
XIV
CI SI NH
N
N N
XV -H
NH
N
I
N
XVI
CI as Na's--"--"
N
NH
=NN
XVIII
CI el CI NH
N NO
NN
XIX
CI
my NH
.,_)NH
N
N
1µ1N =
XX
CI ei Cl I NC=,_.L,N
N
XXI
CI CI
XXII
I
N
N
CI CI
Me0 NH
NL
XXIII
OKI
N
Me0 4111 NH
I
N
XXIV
lit N
HO H
N
XXV
N N
XXVI
NC op CI N H
j, 410 N N
XXVII
NH
.11.
XXVIII
N
CI
NH
I
N
XXIX
11.
N
N N
HN
= 1 NH
N N
XXXI
.4 II
NH
N
XXXII
NH
1,1 is XXXIII
N
rs 410 NH
N N
)CXXIV
NH
N N
X.X.XV
NH
\) N
INN
)0LXVI
NH rN
N 410 N) )00(VII
CI
Me NH
No CI
ilb Neo qw.NH
40 N-) NN
XXXIX
CI
Me0 NH 0 \/L
N N
N N
XL
CI
Me0 NH
40 ND' \)C1 N N
XLI
CI
Me0 NH
NN
XLII
CI
Me0 NH
tNN LN
XLIII
CI ei Me0 NH NH
= N
N N
XLIV
H elN
NH
N
XLV
Ho NH N
NH
N
XLVI
'NH 0"
ti\l+Th N N
XLVII
>v N NH
N N
XLVIII
HO
NH r7-"NH
N
J, N
XLIX
HO el N it NH
0 iNc"
N
HO el N,11 NH
LI
=
N4(1:s NH
NON
N
LII
N
LIII
H 9 Si NH 0F, tN
NS
LIV
Ho lakl N
NH
N
'NNN lb 0 MIPP = =
LV
Ho 411 >-S NH
.1\1 I
N LNH
LVI
H
NH
0"NN
0,,No LVII
H2N,9 LVIII
H 0 el ,NH
II
0 N.õ--LIX
IL Si NH
II
-N N,,) =
LX
HO IP
NH
LXI
NH
N N
LXII
oH 0 SI
N,11 NH r g I
N
,s NH
ON
I
N
LXIV
CN 9 el NH
rtr I
1\r N
LXV
O N.õ) I
N N
LXVI
0 OEt N N
I
LXVII
NH
N 1\1) N
LX VIII
Cl I
N NH
LXIX
H2N1 el NH
N N
LXX
HN
Si NH
N
LX,XI
HN
= I. NH
J1, 1-,NH
N N
LXXII
/ NH
HN
N
LXX.III
/ NH
CI
HN
N
N
N N
L)C.XIV
/ NH
HN
=N N =
LXXV
/ NH
si CI
HN
401 IC)'`
N
LXXVI
/NH
F
HN
N
LXXVII
N N
NN
LXXVIII
HN
"'XXIX
N-NH
HN
N C)---CNH
N
LYOOC
CI tai NH
N) N
LLXXI
CI a O NH
=
N
NH
LXXXII
CI
1111111" NH
N
N N:Th NH
ISO
NH
HON N
N N
LXXXIV
HN9--0b NH N-"
N r\i-) N N
LXXXV
NH
=&,NNIMP
LXXXVI
NH
0 N,,J
I
N
LXXXVII
9 lel NH
NN
N
LXXXVIII
HO
NH
NH
N N N
LXXXIX
NH
N(1"---NH
XC
N sj N NH
XCI
NH
õ.) s,õ,L N
1\
N
XCII
NNSN
XCIII
NH
NH
N
41111) XCIV
CI
0 NH (NH
N
XCV
CI
SI
N
XCVI
NH
N
NO
N
XCVII
>-IS\ Si NH
0"0 I
N
NH
N
XCVIII
OH
NN N
XCIX
Si NH
LN
>õ N
NH
0"0 N
CI
>,-N.is\ 411 NH
N N
NNS
CII
>,-N,A
NH.
N N
CHI
CI
t\ N L,,,õ NH
CIV
NH
0"O
N
CV
H
NH
N
CVI
H
N \
NH
CVII
H
N
NH
00 N'') .õ2.L
N N
CVIII
H
NH
N N-N\
CIX
H
N \ NH
I ISO
N
CX
>, N ,1s\
NH N
N
0"0 N
CXI
NH
NH
0 ' \o tNN
õN
HN-N
CXII
H
>,Ns\
NH HN-N, d 0 N
I
N
CXHI
NH
NN
CXIV
H
>N.,/s\
NH
tN,,N L.0 CXV
HN
NH
N
Nr N=
CXVI
NN 40 õNH
CXVII
CXVIII
N
N
H
CXIX
=
=NH
C) NCN
I
N
CXX
Os/PN/
/
NH
N N
NN
CXXI
\
N 1\1-NN
CXXII
0 z.-NH N-N N
cxxm zo 40 NH rN-N
I
N
CX.XIV
z ki 0zz.-s=LN
N
NN
CXXV
,0 NH
14" NH NH
y NN
CX.XVI
S-NH".
NH
I
N
CXXVII
,0 NH
N
NN
N "Th NH
CXXVIII
S-NH
41) N N
OH
CXXIX
'LN N
I
N
CXXX
HN
Cl gab 411" NH
N
N
NH
CXXXI
IP NH
N
CXXXII
* NH
CXXXIII
N
* NH NH
N N
CXXXIV
* NH
=IN c,,,0 N N
CXXXV
NI, fel s NH
C)/ \
N C) N N
CXXXVI
N H N
N N
CXXXVII
H
N
CXXXVIII
H
N ;s N
N N
CX.,OCIX
N N
N H
N N
CXL
HO 4111' NH
N (::)'=
N NH
CXL I
1410 NH =
N C)NO
NN
CXLII
=rN ON
NN
CXLIII
CI
NH 0õ0 \SI
`'.1\1=%LN ,_,N1H
CXLIV
Cl WI NH
\) N 0, CXLV
NH
H
1\f%i.N/ 410 õõ.NH
CXLVI
NH
_____________________________ N C)Th N
CXLVII
el N N I.NH
H H
N
N N
CXLVIII
=
H H
N 1\1'=
N N
CXLIX
F3C el NH
N
N NH
CL
ON
NH
0 (:),Th =
N N
CLI
H
NH
o N
N
CLII
H
NH
N
CLIII
NH
HN
tin "N N
JL
CLIV
HN
NH
0" 0 N N
CLV
HN
N NH
N
CLVI
NNH
A, NO
N N
CL VII
F3C., 410 NO
N N =
CLVIII
CI
N N
CLIX
el NH
"-N N) N N
CLX
CI so NH
YN
NN
and CLXI
* NH
N N
CLXII
[0056] According to another embodiment of the invention, compounds having the general structure (Z):
B-C (Z) are provided for treatment of various diseases, disorders, and pathologies.
[0057] The general structure (Z) includes two chemically connected moieties B and C.
The moiety B in the general structure (Z) includes any moiety selected from the following group:
CI 0 CI 0 el SI
0 NH 0 NH n 2,,, m el NH NH
,-, 1.NN
H H H = H
HO lei <0 ei II
.13 40 )`N'.IN
I N "N
(NI\l'i 'I\I-N
H H H H
0Si H el N CI
I
HO NH NH 0. NH N NH
0 -,) L'I\Iy 1\1 '-)- N
1 i. t tNN( N'I\1.) NN. N N -z.V
H H H H
NC
si 1010 cl 4/0 N 410 mr NH CI NH NH CI NH
t.NN) I i II
'N I\I.( '1\r N\ kNN) H H H H
' HN \
Si Cl Cl le NH 0 II N lail NH
"N 'N .-..`-'N1 N
I 1 k.
N NI '22,V N NI la,v NN. N N-H H H H
S 0 Cl \NO =
NH NH = NH NH
\/L
1 V I V jN.N. I V
N NI '2?.. ..N1 NI 12.
H H H H
Cl is S .,, r\I I
F NH NH Cl 4111 NH ''.--NH
N I k N N N N N N N
H H H H
0¨\
F
, 0 .4., 0 0 ,.. too Oil F3c 0 NH NH i 3,,.... NH NH
N N
N
I I I
k NN
N N
H H H H
Cl si ID
F3co IP NH F3C NH '0 NH
N-.N
N N- s'a.V .'N NI .2?_V
H H H
? 110 H2N S NH H2N,11 i NH N NH .
' N 0 H
-N)N.
N N" ''a.V ' Nf\l'( H H H
, HN
NH
\ , NH le NH 161 NH 1 NH
\).
N N N \'' Nk N
tLN I V
'7-H H H H
CI lei )0,, 110 N NH
H H
')'''-'1 N N
N)'N. N N.1/4-= tNLNV
-H H H
HN \
N,Ii .. NH II NH . NH
O N
ON'L.'1 N
1 v tNL,Nk 'N-Nk -1\1 NI 12.
H H H
0 -,-OMe 0 Me0 . NH 0 i 6, F3C N N .. NH
''1\1 H H
il-k t V
N NI ''z. .N N
H H H
H 0 el -N,Q1) 41111 NH lail NH
ii NH
0 -=,,,,-1-, i N NI `'2.. I tN.Nk V ''NV
NI ''a.
HH H
,........., .
H 0 141111 0 '-'--.1 0 0 N II N,cli g ii NH NH
>' NH
II
0 N 0 -,.
'N 0 1 'NJ
tN.N.k 1.NNk , 'NeNk H H H
H 0 I.
,, 0 I. rO
NH NH
NH
II
g ,,.N
r\i I V
N N" ''z. N N NN
- .22.
H H H
Ho 0 OS NH
NH
0 Cr 8 .,--..N 0 NL, ')-N'N1 ' .'N N" '22,V N I\ I -s'z,V
H H H
OC` 0 0 H 1110 o 14111 N, 1 1 -= N -..,ii NHNH
NH
II
II
' 0 .N 0 '---'LN 0 'N
t.NN
1=1 N- `'2. 1\1 N
H H H
H
N
* NH -'-''S'II NH . NH
A.
N NI '22. I I
V . N N N NI "42.NK
H H H
m 0 'S NH 1101 I NH NH
II . NH ...--------S \
\O
---- N
I . N N
11(:/ N HN
-'- ' .. Ni.N.( .
'N N .-H H H
NH
r-NI;S\ NH
'-IN \) 'N 0' b HNõ..- ,..),N
I V NiN.\
H H H
, , HN -N HN\ -\
110 F lei HN
H 0 el -õH
NH NH 1411 NH ..---N
N -"N NY)N1 0 ,..) N N NN N N- "'z.V
H H H H
,and H 9 0>,-N, NH
tNN.
H .
[0058] The moiety C in the structure (Z), above, includes any moiety selected from the following group:
0 0....._,------N9 40 . g,11,.o 140 NH el 0,.õ,-, OH * .L 41 N.' O N
.NH
.40 Nõ
40 N,. .,----) ..NH
r Sc?I.,) 0'-, -__\
, scõ. 01 N.Th 1\1.
rNH rN....---...,,,,OH
rNH
=N) 0 c), ei I\1N. N N.) --_,,NH
cF3 NH
N el N.
So Si L--/- N el 9s-N,_ OI
,F3 Nj.1 N N-4110 9,N
N NOH
NH
Nq 1.1 = I .A\I N
HN-N
el NO 40 1\(c) CNH
rN)C NH
,N
00) N NO0 lei r\i`--) ,and [0059] The compounds and methods of the present invention, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, either when administered alone or in combination with other agents (e.g., chemotherapeutic agents or protein therapeutic agents described below) are useful in treating a variety of disorders, including, but not limited to, for example, myeloproliferative disorders, proliferative diabetic retinopathy and other angiogenic-associated disorders including solid tumors and other types of cancer, eye disease, inflammation, psoriasis, and a viral infection. The kinds of cancer that can be treated include, but are not limited to, an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myelogenous leukemia and chronic myelogenous leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.
[0060] Some examples of the diseases and disorders that can be treated also include ocular neovasculariaztion, infantile haemangiornas; organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psbriasis, Type I diabetes and complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, other blood disorders, asthma, rhinitis, atopic, dermatitits, autoimmune thryroid disorders, ulerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, conditions associated with cytokines, and other autoimmune diseases including glomerulonephritisõ scleroderma, chronic thyroiditis, Graves' disease, autoinunune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g., allergic asthma, atopic dermatitis, or allergic rhinitis), chronic active hepatitis, myasthenia graivs, multiple scleroiss, inflammatory bowel disease, graft vs host disease, neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral scelerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, gluatamate neurtoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hyoxia, and platelet aggregation.
[00611 Examples of some additional diseases and disorders that can be treated also include cell mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, HTLVI, Vaicella-Zoster Virus, Human Papilloma Virus), food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.
In one embodiment, the disorder that can be treated is a myeloproliferative disorder. In one embodiment, the myeloproliferative disorder arises due to mutations in a kinase. In one embodiment, the myeloproliferative disorder arises due to gain-of-function of a JAK
family kinase pathway. In one embodiment, the myeloproliferative disorder arises as a result of gene or protein fusions due to gain-of-function of a JAK family kinase pathway.
[0062] Embodiments of the present invention also provide articles of manufacture that can include a packaging material and a pharmaceutical composition contained within the packaging material. The packaginit material can comprise a label which indicates that the pharmaceutical composition can be used for treatment of one or more disorders identified above.
[0063) The pharmaceutical composition can include a compound according to the present invention. In addition to a compound of the present invention, the pharmaceutical may also contain other therapeutic agents, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques known in the art of pharmaceutical formulation.
[00641 Thus, in one embodiment, the invention provides a pharmaceutical composition including a therapeutic agent and a compound of the invention. The compound is present in a concentration effective to treat, for example, cancer or to treat another disease or disorder described above.
10065] The compounds of the invention may be formulated into therapeutic compositions as natural or salt forms. Pharmaceutically acceptable non-toxic salts include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylarnino-ethanol, histidine, procaine, and the like. Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as, for example, hydrochloric, sulfuric, or phosphoric acids, or organic acids such as acetic, citric, p-toluenesulfonic, methanesulfonic acid, oxalic, tartaric, mandelic, and the like.
100661 Salts of the invention can include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the invention can also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p-toluenesulfonic acid, acetic acid, methanesulfonic acid and the like.
Additional excipients which are contemplated for use in the practice of the present invention are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. >all and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, MD (1989). In addition, polymorphs of the invention compounds are included in the present invention.
[00671 Pharmaceutical compositions of the invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders;
sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray;
topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally.
[00681 In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
[0069] The pharmaceutical compositions for the administration of the compounds of this embodiment, either alone or in combination with other therapeutic agents, may conveniently be presented in dosage unit fouli and may be prepared by any of the methods well known in the art of pharmacy. All methods include bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by unifolinly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
[0070] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical- compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.
[0071] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[0072] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Also useful as a solubilizer is polyethylene glycol, for example.
The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0073] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
[0074] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
[0075] Syrups and elixirs may be fonnulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
[0076] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable diluent or solvent or cosolvent or complexing agent or dispersing agent or excipient or combination thereof, for example 1,3-butanediol, polyethylene glycols, polypropylene glycols, ethanol or other alcohols, povidones, various brands of TWEEN surfactant, sodium dodecyl sulfate, sodium deoxycholate, dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, and excipients such as inorganic salts (e.g., sodium chloride), buffering agents (e.g., sodium citrate, sodium phosphate), and sugars (e.g., saccharose and dextrose). Among the acceptable vehicles and solvents that may be employed are water, dextrose solutions, Ringer's solutions and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[0077] Depending on the condition being treated, these pharmaceutical compositions may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences"
(Mack Publishing Co, Easton Pa.). Suitable routes may, for example, include oral or transmucosal administration; as well as parenteral delivery, including intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration. For injection, the phainiaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[0078] The compounds of the present invention may also be administered in the faun of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
[0079] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles).
[0080] In one embodiment, the invention compounds are administered in combination with an anti-inflammatory agent, antihistamines, chemotherapeutic agent, immunomodulator, therapeutic antibody or a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor, to a subject in need of such treatment. While not wanting to be limiting, chemotherapeutic agents include antimetabolites, such as methotrexate, DNA cross-linking agents, such as cisplatinicarboplatin; alkylating agents, such as canbusil; topoisomerase I
inhibitors such as dactinomicin; microtubule inhibitors such as taxol (paclitaxol), and the like.
Other chemotherapeutic agents include, for example, a vinca alkaloid, mitomycin-type antibiotic, bleomycin-type antibiotic, antifolate, colchicine, demecoline, etoposide, taxane, anthracycline antibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin, idarubicin, mithoxanthrone, 4-dimethoxy-daunomycin, 11-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate, adriamycin-14-octanoate, adriamycin-14-naphthaleneacetate, amsacrine, carmustine, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topetecan, oxalaplatin, chlorambucil, methtrexate, lomustine, thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, or mechlorethamine. While not wanting to be limiting, therapeutic antibodies include antibodies directed against the HER2 protein, such as trastuzumab; antibodies directed against growth factors or growth factor receptors, such as bevacizumab, which targets vascular endothelial growth factor, and OSI-774, which targets epidermal growth factor; antibodies targeting integrin receptors, such as Vitaxin (also known as MEDI-522), and the like. Classes of anticancer agents suitable for use in compositions and methods of the present invention include, but are not limited to: 1) alkaloids, including, microtubule inhibitors (e.g., Vincristine, Vinblastine, and Vindesine, etc.), microtubule stabilizers (e.g., Paclitaxel [Taxol], and Docetaxel, Taxotere, etc.), and chromatin function inhibitors, including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide [VP-16], and Teniposide [VM-26], etc.), and agents that target topoisomerase I
(e.g., Camptothecin and Isirinotecan [CPT-11], etc.); 2) covalent DNA-binding agents [alkylating agents], including, nitrogen mustards (e.g., Mechlorethamine, Chlorambucil, Cyclophosphamide, Ifosphamide, and Busulfan [Myleran], etc.), nitrosoureas (e.g., Cartnustine, Lomustine, and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine, Thiotepa, and Mitocycin, etc.); 3) noncovalent DNA-binding agents [antitumor antibiotics], including, nucleic acid inhibitors (e.g., Dactinomycin [Actinomycin D], etc.), anthracyclines (e.g., Daunorubicin [Daunomycin, and Cerubidine], Doxorubicin [Adriamycin], and Idarubicin [Idamycin], etc.), anthracenediones (e.g., anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicamycin (Mithramycin), etc.; 4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex, and Mexate, etc.), purine antimetabolites (e.g., 6-Mercaptopurine [6-MP, Purinethol], 6-Thioguanine [6-TG], Azathioprine, Acyclovir, Ganciclovir, Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine [CdA], and 2'-Deoxycofonnycin [Pentostatin], etc.), pyrimidine antagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosine arabinosides (e.g., Cytosar [ara-C]
and Fludarabine, etc.); 5) enzymes, including, L-asparaginase; 6) hoiniones, including, glucocorticoids, such as, antiestrogens (e.g., Tamoxifen, etc.), nonsteroidal antiandrogens (e.g., Flutamide, etc.), and aromatase inhibitors (e.g., anastrozole [Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin and Carboplatin, etc.); 8) monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides, etc.; 9) biological response modifiers (e.g., interferons [e.g., IFN-.alpha., etc.] and interleukins [e.g., IL-2, etc.], etc.); 10) adoptive immunotherapy; 11) hematopoietic growth factors; 12) agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastases (e.g., Batimistat, etc.); and 17) inhibitors of angiogenesis.
[00811 The phaimaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Examples of other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.
[0082] Other agents that may be administered in combination with invention compounds include protein thera'peutic agents such as cytokines, immunomodulatory agents and antibodies. As used herein the term "cytokine" encompasses chemokines, interleukins, lymphokines, monokines, colony stimulating factors, and receptor associated proteins, and functional fragments thereof. As used herein, the term "functional fragment"
refers to a polypeptide or peptide which possesses biological function or activity that is identified through a defined functional assay.
[0083] The cytokines include endothelial monocyte activating pol)peptide II
(EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF
(M-CSF), IL-1, IL-2, 1L-3, IL-4, IL-5, IL-6, IL-12, and 1L-13, interferons, and the like and which is associated with a particular biologic, morphologic, or phenotypic alteration in a cell or cell mechanism.
[0084] When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one having ordinary skill in the art.
[0085] In the treatment or prevention of conditions which involve cellular proliferation, an appropriate dosage level can generally be between about 0.01 and about 1000 mg per 1 kg of patient body weight per day which can be administered in single or multiple doses. For example, the dosage level can be between about 0.01 and about 250 mg/kg per day; more narrowly, between about 0.5 and about 100 mg/kg per day. A suitable dosage level can be between about 0.01 and about 250 mg/kg per day, between about 0.05 and about 100 mg/kg per day, or between about 0.1 and about 50 mg/kg per day, or about 1.0 mg/kg per day. For example, within this range the dosage can be between about 0.05 and about 0.5 mg/kg per day, or between about 0.5 and about 5 mg/kg per day, or between about 5 and about 50 mg/kg per day. For oral administration, the compositions can be provided in the foim of tablets containing between about 1.0 and about 1,000 mg of the active ingredient, for example, about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1,000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
The compounds can be administered on a regimen of 1 to 4 times per day, such as once or twice per day. There may be a period of no administration followed by another regimen of administration.
[0086] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
[0087] Compounds of the present invention can be used, alone or in combination with an effective amount of a therapeutic antibody (or therapeutic fragment thereof), a chemotherapeutic or an immunotoxic agent, for treatment of tumors.
Illustrative examples of chemotherapeutic agents that can be used for this purpose include doxorubicin, docetaxel, or taxol. It should be further understood that the invention includes combination therapy including a compound of the invention, including but not limited to vasculostatic agents, such as tyrosine, serine or threonine kinase inhibitors, and any chemotherapeutic agent or therapeutic antibody.
C. Examples [0088] The following examples are provided to further illustrate the advantages and features of the present invention, but are not intended to limit the scope of the invention.
EXAMPLE 1. General Methods [0089] All experiments were performed under anhydrous conditions (i.e. dry solvents) in an atmosphere of argon, except where stated, using oven-dried apparatus and employing standard techniques in handling air-sensitive materials. Aqueous solutions of sodium bicarbonate (NaHCO3) and sodium chloride (brine) were saturated. Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F254 plates with visualization by ultraviolet and/or anisaldehyde, potassium permanganate or phosphomolybdic acid dips.
Reverse-phase HPLC chromatography was carried out on Gilson 215 liquid handler equipped with Waters SyinmetiyShieldTM RP18 7 m (40 x 100mm) Prep-Pak cartridge. Mobile phase consisted of standard acetonitrile (ACN) and DI Water, each with 0.1% TFA
added.
Purification was carried out at a flow rate of 40mL/ min. NMR spectra: 1H
Nuclear magnetic resonance spectra were recorded at 500 MHz. Data are presented as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn =
quintet, dd = doublet of =
doublets, m = multiplet, br s = broad singlet), coupling constant (J/Hz) and integration.
Coupling constants were taken directly from the spectra and are uncorrected.
Low resolution mass spectra: Electrospray (ES+) ionization was used. The protonated parent ion (M+H) or fragment of highest mass is quoted. Analytical gradient consisted of 10% ACN
in water ramping up to 100% ACN over 5 min unless otherwise stated.
EXAMPLE 2. N4-(4-Methoxy-phenyI)-pyrimidine-2,4-diamine (Intermediate 1) NH
N
[0090] A mixture of 4-ch1oro-pyrimidin-2-ylamine (0.30 g, 2.3 mmol) and 4-methoxy-phenylamine (0.30 g, 2.4 mmol) were suspended in acetic acid (10 mL) and heated at 100 C
for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7 with 7M
of NaOH solution. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered.
The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (hexane to Et0Ac) to afford the title intermediate 1 (0.23 g, 45%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 3.69 (s, 3H), 5.84 (d, J=
5.8 Hz, 1H), 6.79 (d, J= 9.1 Hz, 2H), 7.63 (d, J= 9.1 Hz, 2H), 7.78 (d, J= 5.8 Hz, 1H), 8.65 (s, 1H);
MS (ESI+): m/z 217 (M+H)+.
EXAMPLE 3. M-(4-Methoxy-pheny1)-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound I) NH
410 (341..D
N
[0091] To synthesize compound I, intermediate 1 described above and intermediate 2 were used. Inteiniediate 2, 142-(4-bromo-phenoxy)-ethyl]Tyrrolidine, shown below is available commercially, and was used as received.
Br =
(2) [0092] A suspension of intermediate 1 (74 mg, 0.34 mmol), intermediate 2 (0.10 g, 0.37 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.05 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3/1; 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 mm. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC to afford the title compound I (20 mg of TFA salt, 11%) as a brown solid. 1H NMR (500 MHz, DMSO-d6): 1.80-1.95 (m, 2H), 1.95-2.10 (m, 2H), 3.05-3.20 (m, 2H), 3.55-3.65 (m, 4H), 3.77 (s, 3H), 4.29 (t, J= 4.9 Hz, 2H), 6.30 (d, J= 6.8 Hz, 1H), 6.96 (d, J=
8.3 Hz, 2H), 6.98 (d, J= 8.3 Hz, 2H), 7.41 (d, J= 8.8 Hz, 2H), 7.55 (d, J= 8.8 Hz, 2H), 7.89 (d, J= 6.2 Hz, 1H), 9.87 (br s, 1H), 10.22 (br s, 1H), 10.44 (br s, 1H); MS (ESI+): nilz 406 (M+H)4.
EXAMPLE 4. 4-[4-(4-Methoxy-phenylamino)-pyrimidin-2-0aminol-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (Compound II) NH
N
j, OH
II
[0093] To synthesize compound II, intermediate 1 described above and intermediate 3 were used. Intermediate 3, 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, the formula of which is shown below, was synthesized from 4-bromophenylsulfonylchloride and 2-aminoethylpyrrolidine, using commonly known synthetic techniques.
-N'Nr'D
Br [0094] A suspension of intermediate 1 described above (70 mg, 0.32 mmol), intermediate 3 (0.12 g, 0.36 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.05 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3/1; 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC to afford the title compound II (0.16 g of TFA salt, 85%) as a white solid. 1H
NMR (500 MHz, DMSO-d6): 1.80-1.95 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.23 (q, J=
5.8 Hz, 2H), 3.50-3.60 (m, 2H), 3.79 (s, 3H), 6.41 (d, J= 6.8 Hz, 1H), 6.99 (d, J= 8.9 Hz, 2H), 7.43 (d, J= 8.9 Hz, 2H), 7.71 (d, J= 8.6 Hz, 2H), 7.85-7.95 (m, 2H), 7.96 (t, J=
6.1 Hz, 1H), 8.02 (d, J= 6.2 Hz, 1H), 9.64 (br s, 1H), 10.21 (br s, 1H), 10.71 (br s, 1H);
MS (ESI+): nilz 469 (M+H)+.
EXAMPLE 5. 4-14-(4-Hydroxy-phenylamino)-pyrimidin-2-ylaminol-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (Compound III) HO is NH
II JOH
Ill [0095] To a solution of compound II described above (50 mg, 0.09 mmol) in DCM
(6 mL) at room temperature was added I3Br3 (0.1 mL) and the mixture stirred at room temperature for 2.5 h. The reaction was quenched with saturated NaHCO3 solution until the pH-7 and the mixture extracted with Et0Ac (30 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the resulting solid re-dissolved in minimum of Et0Ac. Hexane was added until solid crushed out and the title compound III was filtered as a white solid (25 mg, 64%) without further purification. 1H NMR (500 MHz, DMSO-d6): 1.55-1.65 (m, 4H), 2.30-2.40 (m, 4H), 2.43 (t, J= 7.0 Hz, 2H), 2.82 (t, J= 6.6 Hz, 2H), 6.20 (d, J= 5.8 Hz, 1H), 6.70 (d, J=
8.8 Hz, 2H), 7.40 (d, J= 8.6 Hz, 2H), 7.64 (d, J= 8.8 Hz, 2H), 7.92 (d, J= 8.4 Hz, 2H), 8.03 (d, J- 5.5 Hz, 1H), 8.93 (s, 1H), 9.08 (br s, 1H), 9.70 (s, 1H); MS (ESI+): in/z 455 (M+H)+.
EXAMPLE 6. 4-(4-Chloro-pyrimidin-2-ylamino)-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (Intermediate 4) ci N
.,1õ. 0 H
=N N
[0096] A mixture of 4-chloro-pyrimidin-2-ylamine (1.0 g, 7.8 mmol), above-described intermediate 3 (2.6 g, 7.8 mmol), Pd(OAc)2 (90 mg, 0.40 mmol), Xantphos (0.50 g, 0.86 mmol) and potassium tert-butoxide (2.2 g, 20 mmol) were suspended in dioxane (30 mL) and heated at reflux under the argon atmosphere for 16 h. The mixture was poured into water (30 mL) and extracted with Et0Ac (60 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 25% Me0H/DCM) to afford the title intermediate 4 (0.15 g, 5%) as a brown solid. MS (ESI+): inlz 382 (M+H)+.
EXAMPLE 7. 4-[4-(3-Methoxy-phenylamino)-pyrimidin-2-ylaminol-N-(2-pyrrolidin-1-yl-ethy1)-benzenesulfonamide (Compound IV) NH
b.
N
OH
N
Iv [0097] A mixture of the above described intermediate 4 (0.10 g, 0.26 mmol) and 3-methoxy-phenylamine (0.05 mL, 0.45 mmol) were suspended in acetic acid (6 mL) and heated at 100 C for 1.5 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound IV (55 mg of TFA salt, 36%) as a white solid. 1H NMR
(500 MHz, DMSO-d6): 1.80-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.24 (q, J=
6.0 Hz, 2H), 3.50-3.60 (m, 2H), 3.73 (s, 3H), 6.40 (d, J= 6.3 Hz, 1H), 6.68 (d, J= 7.3 Hz, 1H), 7.18 (d, J= 8.2 Hz, 1H), 7.26 (t, J= 8.0 Hz, 1H), 7.30 (s, 1H), 7.72 (d, J= 8.9 Hz, 2H), 7.91 (t, J-6.1 Hz, 1H), 7.95 (d, J= 8.7 Hz, 2H), 8.10 (d, J= 6.2 Hz, 1H), 9.59 (br s, 1H), 9.87 (br s, 1H), 10.38 (br s, 1H); MS (ESI+): m/z 469 (M+H)+.
EXAMPLE 8. 4-[443-Hydroxy-phenylamino)-pyrimidin-2-ylaminol-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (Compound V) HO NH
N N
NN J
H
V
[0098] To a solution of the above-described compound IV (30 mg, 0.05 mmol) in DCM (6 mL) at room temperature was added BBr3 (0.1 mL) and the mixture stirred at room temperature for 2.5 h. The reaction was quenched with saturated NaHCO3 solution until the pH-7 and the mixture extracted with Et0Ac (30 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by HPLC to afford the title compound V (13 mg of TFA salt, 46%) as an off white solid. 1H NMR (500 MHz, DMSO-d6): 1.80-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.20-3.30 (in, 2H), 6.39 (d, J= 6.3 Hz, 1H), 6.53 (d, J= 7.2 Hz, 1H), 7.01 (d, J
= 9.2 Hz, 1H), 7.09 (s, 1H), 7.14 (t, J= 8.1 Hz, 1H), 7.73 (d, J= 8.8 Hz, 2H), 7.90 (t, J= 6.2 Hz, 1H), 7.97 (d, J= 8.8 Hz, 2H), 8.08 (d, J= 6.4 Hz, 1H), 9.48 (br s, 1H), 9.57 (br s, 1H), 9.86 (br s, 1H), 10.41 (br s, 1H); MS (ESI+): m/z 455 (M+H)+.
EXAMPLE 9. Benzo[1,31dioxo1-5-y1-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 5) <0 Ai I
'NN CI
[0099] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5-bromo-benzo[1,3]dioxole (0.45 g, 2.2 mmol), Pd(OAc)2 (30 mg, 0.13 mmol), Xantphos (0.15 g, 0.26 mmol) and potassium tert-butoxide (0.45 g, 4.0 mmol) were suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 16 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated ill vacuo. The residue was purified by flash chromatography on silica gel (hexane to 50% Et0Ac/hexane) to afford the title intermediate 5 (0.10 g, 18%) as a white solid. MS (ESI+): m/z 264 (M+H) .
EXAMPLE 10. /V4-Senzo[1,31dioxo1-5-y1-5-methyl-N2-P1-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound VI) <0 N 40:1 C)Nit.D
N N
VI
[0100[ To synthesize compound VI, intermediate 5 described above and inteunediate 6 were used. Intermediate 6, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine, the fonnula of which is shown below, was synthesized in two steps, first by alkylation of 4-nitrophenol using 2-chloroethylpyrrolidine, followed by reduction to yield the aniline derivative.
[0101] Commonly known synthetic techniques were used to synthesize intermediate 6. A
mixture of the above-described intermediate 5 (90 mg, 0.34 mmol), intermediate 6 (95 mg, 0.46 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), Xantphos (30 mg, 0.05 mmol) and cesium carbonate (0.30 g, 0.9 mmol) were suspended in dioxane (10 mL) and heated at reflux under the argon atmosphere for 20 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo.
The residue was purified by HPLC to afford the title compound VI (40 mg of TFA
salt, 21%) as a brown solid. 111 NMR (500 MHz, DMSO-d6): 1.85-1.95 (m, 2H), 1.95-2.05 (m, 2H), 2.13 (s, 3H), 3.10-3.20 (m, 2H), 4.26 (t, J= 5.0 Hz, 2H), 6.07 (s, 2H), 6.90-7.00 (m, 4H), 7.19 (s, 1H), 7.37 (d, J= 9.0 Hz, 2H), 7.84 (s, 1H), 9.60 (hr s, 1H), 9.89 (br s, 1H), 10.32 (hr s, 1H); MS (ESI+): nz/z 434 (M+H)+.
EXAMPLE 11. (4-Chloro-3-methoxy-pheiry1)-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 7) I
CI
[0102] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol), brorno-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% Et0Ac/hexane) to afford the title intermediate 7 (0.55 g, 55%) as a yellow solid. ill NMR (500 MHz, DMSO-d6): 2.18 (s, 3H), 3.85 (s, 3H), 7.35 (dd, J= 8.6 Hz, J= 2.3 Hz, 1H), 7.39 (d, J= 8.7 Hz, 1H), 7.56 (d, J=
2.3 Hz, 1H), 8.09 (d, J= 0.9 Hz, 1H), 8.91 (s, 1H); MS (ESI+): m/z 284 (M+H) .
EXAMPLE 12. (4-Chloro-3-rnethoxy-pheny1)-(2-ehloro-5-methyl-pyrimidin-4-y1)-methyl-amine (Intermediate 8) CI
N
NCI
[0103] A suspension of intermediate 7 (0.50 g, 1.8 mmol) and sodium hydride (60% in mineral oil, 0.15 g, 3.8 mmol) in THF (10 mL) was stirred under the argon atmosphere at 0 C for 5 mm. Methyl iodide (0.15 mL, 2.4 mmol) was syringed at the same temperature to the above mixture. The resulting solution was stirred from 0 C to room temperature over 15 min and further stirred at room temperature for additional 17 h. The reaction was quenched with water (10 mL) and then extracted with Et0Ac (30 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexane to 20%
Et0Ac/hexane) to afford the title intermediate 8 (0.20 g, 38%) as a white solid. MS (ESI+):
nilz 298 (M+H)+.
EXAMPLE 13. N2-(4-(2-(pyrrolidin-1-ybethoxy)pheny1)-N4-(4-chloro-3-methoxvphenyll-N4,5-dimethvlpyrimidine-2,4-diamine (Compound VII) Cl ON
N N
VII
[0104] A mixture of intermediate 8 (0.15 g, 0.49 mmol) and intermediate 6 (0.15 g, 0.73 mmol), each of which intemiediates is described above, were suspended in acetic acid (8 mL) and heated at 100 C for 17 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH solution. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound VII (0.14 g of TFA salt, 49%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 1.85-1.95 (m, 2H), 2.00-2.10 (m, 2H), 3.08-3.18 (m, 2H), 3.46 (s, 3H), 3.55-3.65 (m, 4H), 3.85 (s, 3H), 4.27 (t, J= 5.0 Hz, 2H), 6.86 (d, J= 7.4 Hz, 1H), 7.01 (d, J= 9.0 Hz, 2H), 7.15 (s, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 8.9 Hz, 2H), 7.83 (s, 1H), 9.85 (br s, 1H), 10.04 (br s, 1H), 10.32 (br s, 1H); MS
(ESI+): ni/z 468 (M+H)+.
EXAMPLE 14. t-5-meth rhnidiu--di1oro- hen 1 -amine (Intermediate 9) CI
NH
N
CI
[0105] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 1-bromo-4-chloro-benzene (0.60 g, 3.1 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% Et0Aciltexane) to afford the title intermediate 9 (0.15 g, 28%) as a pale yellow solid. MS (ESI+): nilz 254 (M+H)+.
EXAMPLE 15. /V4-(4-Chloro-pheny1)-5-methyl-N244-(2-pyrrolidin4-yl-ethoxy)-- phenyn-pyrimidine-2,4-diamine (Compound VIII) CI, NH
N (21NLD
N N
VIII
[0106] A mixture of the above-described intermediates 9 (0.15 g, 0.60 mmol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 mL) and heated at 100 C for 6 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH
solution. The resulting brown solid was filtered and further purified by HPLC
to afford the title compound VIII (38 mg of TFA salt, 12%) as a brown oil. 1H NMR (500 MHz, d6): 1.80-1.95 (m, 2H), 2.00-2.10 (m, 2H), 2.15 (s, 3H), 3.10-3.20 (m, 2H), 3.55-3.65 (m, 4H), 3.77 (s, 3H), 4.28 (t, J= 5.0 Hz, 2H), 6.95 (d, J= 9.0 Hz, 2H), 7.38 (d, J= 8.9 Hz, 2H), 7.42 (d, J= 8.9 Hz, 2H), 7.62 (d, J= 8.8 Hz, 2H), 7.90 (s, 1H), 9.48 (br s, 1H), 9.84 (br s, 1H), 10.10 (br s, 1H); MS (ESI+): n2/z 424 (M+H)+.
EXAMPLE 16. 244-Amino-phenoxy)-ethanol (Intermediate 10) [0107] A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in Me0H (30 mL) was flushed with argon and then charged with Pd/C (10% by wt). The mixture was evacuated under house vacuum and then refilled with hydrogen from hydrogen balloon. The cycle was repeated again and the mixture stirred at room temperature for 2 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo to furnish the title intermediate 10 (1.8 g, 99%) as a brown solid.
MS (ESI+): ni/z 154 (M+H)+.
EXAMPLE 17. 2-14-1-4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylaminol-phenoxyl-ethanol (Compound IX) mr NH
'NN 410 C'OH
N
IX
[0108] A suspension of the above described intermediates 7 (50 mg, 0.17 mmol), 10 (40 mg, 0.26 mmol), Pd2(dba)2 (8 mg, 0.01 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 mm. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM.
The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexane to Et0Ac) to afford the title compound IX (14 mg, 21%) as a light brown solid. 11-1 NMR (500 MHz, DMSO-d6): 2.10 (s, 3H), 3.69 (t, J= 5.3 Hz, 2H), 3.75 (s, 3H), 3.92 (t, J=
5.1 Hz, 2H), 4.83 (t, J= 5.6 Hz, 1H), 6.78 (d, J= 9.0 Hz, 2H), 7.29 (d, J= 8.5 Hz, 1H), 7.43 (dd, J= 8.6 Hz, J= 2.2 Hz, 1H), 7.48 (d, J= 2.3 Hz, 1H), 7.52 (d, J= 9.0 Hz, 2H), 7.88 (s, 1H), 8.31 (s, 1H), 8.80 (s, 1H); MS (ESI+): 771/Z 401 (M+H)+.
EXAMPLE 18. 5-Methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Intermediate 11) 1401 ()NO
\ NN
[0109] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.13 g, 0.87 mmol) and the above described intermediate 6 (0.30 g, 1.5 mmol) were suspended in acetic acid (8 mL) and heated at 100 C for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH solution. The resulting solid was filtered (30 mg) and washed with ether. The filtrate was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated to afford the additional solid (0.2 g), which were combined with the first batch and afforded the title intermediate 11 (0.23 g, 85%) as a light brown solid. Ili NMR (500 MHz, DMSO-d6): 1.65-1.70 (m, 4H), 1.89 (s, 3H), 2.74 (t, J= 6.0 Hz, 2H), 3.98 (t, J= 6.1 Hz, 2H), 6.30 (s, 2H), 6.78 (d, J= 9.1 Hz, 2H), 7.62 (d, J= 9.1 Hz, 2H), 7.64 (s, 1H), 8.50 (s, 1H); MS (ESI+): m/z 314 (M+H)+.
EXAMPLE 19. 5-Methyl-NI-phenyl-N2-14-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound X) () N
X
[0110] A suspension of the above-described intermediate 11 (25 mg, 0.08 mmol), bromobenzene (0.05 mL, 0.50 imnol), Pd2(dba)2 (5 mg, 0.006 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate (70 mg, 0.21 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% Me0H/DCM) to afford the title compound X (10 mg, 32%) as alight brown solid. 1H NMR (500 MHz, DMSO-d6): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.48-2.58 (m, 4H), 2.75-2.82 (m, 2H), 4.00 (t, J= 5.9 Hz, 2H), 6.77 (d, J= 9.0 Hz, 2H), 7.04 (t, J= 7.3 Hz, 1H), 7.32 (t, J= 7.9 Hz, 2H), 7.54 (d, J= 9.0 Hz, 2H), 7.71 (d, J=
7.8 Hz, 2H), 7.84 (s, 1H), 8.20 (s, 1H), 8.76 (s, 1H); MS (ESI+): m/z 390 (M+H)+.
EXAMPLE 20. (4-Chloro-3-fluoro-pheny1)-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 12) CI, NH
N
I
CI
[0111] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mrnol), 4-Bromo-1-chloro-2-fluoro-benzene (1.0 g, 4.8 mmol), Pd2(dba)3 (0.16 g, 0.17 mmol), Xantphos (0.20 g, 0.34 mmol) and cesium carbonate (2.3 g, 7.0 mmol) were suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 15 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% Et0Ac/hexane) to afford the title intermediate 12 (0.75 g, 80%) as an off white solid. MS (ESI+): m/z 272 (M+H)+.
EXAMPLE 21. /V4-(4-Chloro-3-fluoro-phenyl)-5-methyl- N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound XI) CI
N H
N
I
N
XI
[0112] A mixture of the above-described inten-nediates 12 (0.20 g, 0.74 mmol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 mL) and heated at 100 C for 6 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH
solution. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 30% Me0H/DCM) to afford the title compound XI (90 mg, 28%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 1.65-1.71 (m, 4H), 2.10 (s, 3H), 2.45-2.55 (m, 4H), 2.77 (t, J= 6.0 Hz, 2H), 4.01 (t, J= 6.0 Hz, 2H), 6.82 (d, J= 9.0 Hz, 2H), 7.44 (t, J=
8.8 Hz, 1H), 7.50 (d, J= 9.0 Hz, 2H), 7.55 (dd, J= 8.9 Hz, J= 2.0 Hz, 1H), 7.91 (s, 1H), 8.07 (dd, J= 12.5 Hz, J= 2.0 Hz, 1H), 8.43 (s, 1H), 8.90 (s, 1H); MS (ESI+): m/z 442 (M+H)+.
EXAMPLE 22. N4-(4-Chloro-3-methoxy-phenyI)-5-methyl-N2-(4-morpholin-4-ylmethyl-phenyl)-pyrimidine-2,4-diamine (Compound XII) CI
t4111 NO
N N ) XII
[0113] A suspension of the above-described intermediate 7 (50 mg, 0.17 mmol), 4-morpholin-4-ylmethyl-phenylamine (50 mg, 0.26 mmol), Pd2(dba)2 (8 mg, 0.009 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC to afford the title compound XII (40 mg of TFA salt, 43%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6): 2.16 (s, 311), 3.05-3.15 (m, 2H), 3.10-3.20 (m, 2H), 3.60-3.70 (m, 2H), 3.90-4.00 (m, 2H), 4.28 (s, 2H), 4.01 (t, J= 6.0 Hz, 2H), 7.25-7.35 (m, 3H), 7.35-7.41 (m, 2H), 7.65 (d, J.= 8.3 Hz, 211), 7.98 (s, 1H), 9.10 (br s, 1H), 9.86 (br s, 1H), 9.95 (br s, 1H); MS (ESI+): tn/z 440 (M+H)+.
EXAMPLE 23. Benzoibithiophen-5-y142-chloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 13) NH
N
I
N CI
[0114] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5-bromo-benzo[b]thiophene (0.6 g, 2.8 nn-nol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% Et0Ac/hexane) to afford the title interinediate 13 (0.23 g, 40%) as a white solid. MS (ESI+): in/z 276 (M+H)+.
EXAMPLE 24. N4-Benzo[b]thiophen-5-y1-5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyi]-pyrimidine-2,4-diamine (Compound XIII) NH
LI
= N
N N
XIII
[0115] A mixture of the above-described intermediates 13 (0.23 g, 0.83 mmol) and 6 (0.35 g, 1.7 mmol) were suspended in acetic acid (8 mL) and heated at 100 C for 1 d. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure.
The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH
solution.
The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated.
The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 15% Me0H/DCM) to afford the title compound XIII (0.13 g, 35%) as a white solid. Ill NMR (500 MHz, DMSO-d6): 1.65-1.75 (m, 4H), 2.12 (s, 3H), 2.50-2.62 (m, 4H), 2.75-2.85 (in, 2H), 3.99 (t, J= 5.9 Hz, 2H), 6.70 (d, J= 9.0 Hz, 2H), 7.36 (d, J- 5.4 Hz, 1H), 7.51 (d, J= 9.1 Hz, 2H), 7.61 (dd, J= 8.7 Hz, J= 2.0 Hz, 1H), 7.74 (d, J
5.4 Hz, 1H), 7.85 (d, J- 0.8 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 1.7 Hz, 1H), 8.34 (s, 1H), 8.76 (s, 1H); MS (ESI+): in/z 446 (M+H)+.
EXAMPLE 25. Benz [b] thiophen-3-y1-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 14) NH
[0116] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 3-bromo-benzo[b]thiophene (0.6 g, 2.8 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% Et0Ac/hexane) to afford the title intermediate 14 (65 mg, 11%) as a yellow solid. MS (ESI+): m/z 276 (M+H)+.
EXAMPLE 26. NI-Benzo[b]thiophen-3-y1-5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound XIV) =
NH
N
XIV
[0117] A mixture of the above-described intermediates 14 (50 mg, 0.18 mmol) and 6 (0.10 g, 0.48 mmol) was suspended in acetic acid (8 mL) and heated at 100 C for 15 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (10 mL) and neutralized to pH-7 with 7M of NaOH
solution. The resulting solution was extracted with Et0Ac (20 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 15% Me0H/DCM) to afford the title compound XIV (10 mg, 13%) as an off white solid. IHNMR (500 MHz, DMSO-d6): 1.70-1.80 (in, 4H), 2.19 (s, 3H), 2.65-2.80 (in, 4H), 2.85-3.00 (in, 2H), 3.98-4.03 (in, 2H), 6.63 (d, J= 8.8 Hz, 2H), 7.37 (d, J¨ 8.6 Hz, 2H), 7.38-7.45 (in, 2H), 7.79-7.83 (in, 1H), 7.87 (s, 1H), 7.90-8.03 (in, 1H), 8.33 (s, 1H), 8.78 (s, 1H); MS (ESI+): in/z 446 (M+H)+.
EXAMPLE 27. (2-Chloro-5-methyl-pyrimidin-4-y1)-(3-ehloro-phenyl)-amine (Intermediate 151 CI NH
N
CI
[0118] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 1-bromo-3-chloro-benzene (0.60 g, 3.1 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% Et0Ac/hexane) to afford the title intermediate 15 (0.30 g, 56%) as a pale yellow solid. MS (ESI+): nz/z 254 (M+H)+.
EXAMPLE 28. N4-(3-Chloro-phenyl)-5-methyl-N2-14-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound XV) CI NH
NN
XV
[01191 A
mixture of the above-described inteiluediates 15 (0.15 g, 0.59 mmol) and 6 (0.25 g, 1.2 mmol) was suspended in acetic acid (8 mL) and heated at 100 C for 21 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH
solution. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 10% Me0H/DCM) to afford the title compound XV (60 mg, 24%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.50-2.60 (m, 4H), 2.78-2.83 (m, 2H), 4.01 (t, J= 5.9 Hz, 2H), 6.81 (d, J= 9.1 Hz, 2H), 7.05-7.08 (m, 1H), 7.32 (t, J= 8.1 Hz, 1H), 7.52 (d, J.= 9.0 Hz, 2H), 7.71 (d, J 8.3 Hz, 1H), 7.85 (t, J= 2.1 Hz, 1H), 7.89 (d, J= 0.7 Hz, 1H), 8.33 (s, 1H), 8.86 (s, 1H); MS (ESI+): mlz 424 (M+H)+.
EXAMPLE 29. 3-Bromo-N-methyl-benzamide (Intermediate 16) (110 Br [0120] A solution of 3-bromo-benzoyl chloride (2.93 g, 13.3 mmol, 1 eq) in 30mL THF
was stirred vigorously and treated with 2.0M methylamine in THF (15 mL, 29.4 mmol, 2.2 eq). A white precipitate was observed and the reaction was allowed to stir for 20 minutes.
Reaction was then poured onto ethyl acetate (100 mL) and washed with water (2 x 150 mL) and brine (1 x 150 mL). Organic phase cut from aqueous phase and dried over sodium sulfate, filtered and evaporated to afford the title intermediate 16 as a white powder. (2.29g, 82% yield).
EXAMPLE 30. 3-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-N-methyl-benzamide (Intermediate 17) NH
ON
CI
[0121] In a dry 50 mL round bottom flask, 2-chloro-5-methyl-pyrimidin-4-ylamine (0.3 g, 2.09 mmol, 1 equiv), 3-bromo-N-methyl-benzamide (0.489g, 2.29 mmol, 1.1 equiv), cesium carbonate (2.04g, 6.27 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene , (0.242 g, 0.418 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.191 g, 0.209 mmol, 0.1 equiv) were combined. Reactants were diluted with dioxane (20 mL), flushed with argon and outfitted with reflux condenser. Reaction was heated to reflux for 16 hours.
Reaction was then transferred into centrifuge tube, spun down, decanted and evaporated.
Resulting yellow solids were diluted with DCM and adsorbed onto silica gel.
Chromatography (gradient of 50% ethyl acetate in hexanes up to 100% ethyl acetate) afforded the title intermediate 17 as a pale yellow powder (0.25 g, 43%
yield). MS (ESI+):
277.01 (M+H), r.t. 1.92 mm.
EXAMPLE 31. N-Methyl-3-15-methyl-2-14-(2-pyrrolidin-1-yl-ethoxy)-phenylaminol-pyrimidin-4-ylaminol-benzamide TFA salt (Compound XVI) NH
N
XVI
[0122] The above-described intermediate 17 (0.068 g, 0.246 mmol, 1 eq), 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (0.061 g, 0.296 mmol, 1.2 eq), cesium carbonate (0.241 g, 0.74 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.029 g, 0.05 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.023 g, 0.025 mmol, 0.1 equiv) were combined in 15m1microwave vessel. Reactants were then diluted with 7 ml dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification afforded the TFA salt of the title product XVI
(0.084 g, 76%). MS (ESI+): 447.20 (M+H), r.t. = 1.53 min. 1H NMR (DMSO-d6): 8 1.87-1.91 (m, 2H), 2.02-2.06 (m, 2H), 2.16 (s, 3H), 2.79 (d, J=4.6 Hz, 3H), 3.11-3.15 (m, 2H), 3.57-3.61 (m, 5H), 4.23 (t, J=5.0 Hz, 3H), 6.84 (d, J=8.8 Hz, 2H), 7.34(d, J=8.9 Hz, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.68-7.70 (m, 2H), 7.93 (s, 1H), 8.00 (s, 1H), 8.46-8.47 (m, 1H), 9.80 (bs, 1H), 9.93 (bs, 1H) 10.41 (bs, 1H).
EXAMPLE 32. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-14-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine TFA salt (Compound XVII) Cl gib 0 giF NH
"N
N
XVII
[0123] The above-described intermediate 7 (0.083 g, 0.293 mmol, 1 eq), 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (0.073 g, 0.352 mmol, 1.2 eq), cesium carbonate (0.287 g, 0.879 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.034 g, 0.059 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.027 g, 0.029 mmol, 0.1 equiv) were combined in 15ml microwave vessel. Reactants were then diluted with 7 ml dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification afforded the TFA salt of the title product XVII (0.1 g, 75%). MS (ESP-): 454.13 (M+H), r.t. 1.82 min. 1H NMR (DMSO-do): 5 1.87-1.90 (m, 2H), 2.02-2.05 (m, 2H), 2.15 (s, 3H), 3.11-3.14(m, 2H), 3.58-3.61 (m, 5H), 3.70 (s, 3H), 4.26 (t, J-5.0 Hz, 3H), 6.91 (d, J=8.9 Hz, 2H), 7.23 (m, 1H), 7.34-7.4 (m, 4H), 7.93 (s, 1H), 9.63 (bs, 1H), 9.96 (bs, 1H) 10.40 (bs, 1H).
EXAMPLE 33. N-(2-Chloro-5-methyl-pyrimidin-4-y1)-N',N'-dimethvl-benzene-1,3-diamine (Intermediate 18) NH
=L N
LNCI
[0124] 2-Chloro-5-methyl-pyrimidin-4-ylamine (0.343 g, 2.38 mmol, 1 equiv), (3-bromo-pheny1)-dimethyl-amine (0.524g, 2.62 mmol, 1.1 equiv), cesium carbonate (2.3 g, 7.15 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.276 g, 0.476 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.218 g, 0.238 mmol, 0.1 equiv) were combined in 30m1 microwave vessel. Reactants were then diluted with 12m1 dioxane and microwaved for 25 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. Resulting solids were diluted with DCM and adsorbed onto silica gel.
Chromatography (gradient of 0% methanol in DCM up to 25% methanol in DCM) afforded the title intermediate 18 as orange solid (0.184 g, 29% yield). MS (ESI+):
263.02 (M+H), r.t.
=-- 1.72 mm.
EXAMPLE 34. /V4-(3-Dimethylamino-phenyl)-5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine TFA salt (Compound XVIII) NH
I
N 401 C)10 XVIII
[0125] The above-described intermediate 18 (0.092 g, 0.35 mmol, 1 eq), 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.087 g, 0.42 mmol, 1.2 eq), cesium carbonate (0.343 g, 1.05 mmol, 3 equiv), 4,5-bis(diphenyl phosphino)-9,9-dimethyl xanthene (0.041 g, 0.0702 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.032 g, 0.035 mmol, 0.1 equiv) were combined in a 15 ml microwave vessel. Reactants were then diluted with 7m1 dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification provided the TFA salt of the title compound XVIII
(0.035 g, 23%). MS (ESI+): 433.21 (M+H), r.t. = 1.52 min. 1H NMR (DMSO-d6): 6 1.87-1.90 (m, 2H), 2.03-2.06 (m, 2H), 2.15 (s, 3H), 2.87 (s, 6H), 3.12-3.15 (m, 2H), 3.57-3.60 (m, 4H), 3.70 (s, 3H), 4.25 (t, J=5.0 Hz, 3H), 6.34 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 6.82-6.90 (m, 4H), 7.20 (t, J=8.0 Hz, 1H), 7.39 (d, J=9.1 Hz, 2H), 7.85 (s, 1H), 9.63 (bs, 1H), 9.90 (bs, 1H) 10.39 (bs, 1H).
EXAMPLE 35. (2-Chloro-5-methyl-pyrimidin-4-y1)-(3,4-diehloro-phenyl)-amine (Intermediate 19) CI ei CI NH
N
I
CI
[0126] 2-chloro-5-methyl-pyrimidin-4-ylamine (0.408 g, 2.83 mmol, 1 equiv), 4-Bromo-1,2-dichloro-benzene (0.704 g, 3.12 minol, 1.1 equiv), cesium carbonate (2.8 g, 8.49 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.328 g, 0.57 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.26 g, 0.283 mmol, 0.1 equiv) were combined in 30m1 microwave vessel. Reactants were then diluted with 12ml dioxane and microwaved for 25 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. Resulting solids were diluted with DCM and adsorbed onto silica gel.
Chromatography (gradient of 15% ethyl acetate in hexanes up to 80% ethyl acetate in hexanes) afforded the title intermediate 19 as a pale yellow powder (0.366 g, 45% yield). MS
(ESI+): 287.97 (M+H), r.t. = 3.12 min.
EXAMPLE 36. N4-(3õ4-Dichloro-phenyl)-5-methyl-N244-(2-pyrrolidin4-171-ethor4)-phenyll-pyrimidine-2,4-diamine TFA salt (Compound XIX) CI
CI N H
N
N N
XIX
[0127] The above-described intermediate 19 (0.09 g, 0.313 mmol, 1 eq), 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.078 g, 0.376 mmol, 1.2 eq), cesium carbonate (0.307 g, 0.941 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.036 g, 0.063 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.029 g, 0.0314 mmol, 0.1 equiv) were combined in 15m1 microwave vessel. Reactants were then diluted with 7m1 dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification provided the TFA salt of the title compound XIX (0.056 g, 39%). MS (ESI+): 458.1 (M+H), r.t. = 1.93 min. 111 NMR (DMSO-d6): 5 1.87-1.91 (m, 2H), 2.03-2.06 (m, 2H), 2.14 (s, 3H), 3.12-3.15 (m, 3H), 3.57-3.60 (m, 4H), 4.26 (t, J=5.0 Hz, 2H), 6.97 (d, J=9.0 Hz, 1H), 7.40 (d, J=9 Hz, 2H), 7.60 (s, 2H), 7.97 (d, J=15.35 Hz, 2H), 9.46 (bs, 1H), 9.89 (bs, 1H) 10.17 (bs, 1H).
EXAMPLE 37. 4-{3-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylaminol-benzyll-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 20) CI is N
N N
[0128] (4-Chloro-3-methoxy-pheny1)-(2-chloro-5-methyl-pyrimidin-4-y1)-amine (0.092 g, 0.325 mmol, 1 eq), 4-(3-amino-benzyp-piperazine-1-carboxylic acid tert-butyl ester (0.114 g, 0.39 mmol, 1.2 eq), cesium carbonate (0.318 g, 0.975 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.038 g, 0.065 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.03 g, 0.0325 mmol, 0.1 equiv) were combined in a
NN
XIII
NH
N
XIV
CI SI NH
N
N N
XV -H
NH
N
I
N
XVI
CI as Na's--"--"
N
NH
=NN
XVIII
CI el CI NH
N NO
NN
XIX
CI
my NH
.,_)NH
N
N
1µ1N =
XX
CI ei Cl I NC=,_.L,N
N
XXI
CI CI
XXII
I
N
N
CI CI
Me0 NH
NL
XXIII
OKI
N
Me0 4111 NH
I
N
XXIV
lit N
HO H
N
XXV
N N
XXVI
NC op CI N H
j, 410 N N
XXVII
NH
.11.
XXVIII
N
CI
NH
I
N
XXIX
11.
N
N N
HN
= 1 NH
N N
XXXI
.4 II
NH
N
XXXII
NH
1,1 is XXXIII
N
rs 410 NH
N N
)CXXIV
NH
N N
X.X.XV
NH
\) N
INN
)0LXVI
NH rN
N 410 N) )00(VII
CI
Me NH
No CI
ilb Neo qw.NH
40 N-) NN
XXXIX
CI
Me0 NH 0 \/L
N N
N N
XL
CI
Me0 NH
40 ND' \)C1 N N
XLI
CI
Me0 NH
NN
XLII
CI
Me0 NH
tNN LN
XLIII
CI ei Me0 NH NH
= N
N N
XLIV
H elN
NH
N
XLV
Ho NH N
NH
N
XLVI
'NH 0"
ti\l+Th N N
XLVII
>v N NH
N N
XLVIII
HO
NH r7-"NH
N
J, N
XLIX
HO el N it NH
0 iNc"
N
HO el N,11 NH
LI
=
N4(1:s NH
NON
N
LII
N
LIII
H 9 Si NH 0F, tN
NS
LIV
Ho lakl N
NH
N
'NNN lb 0 MIPP = =
LV
Ho 411 >-S NH
.1\1 I
N LNH
LVI
H
NH
0"NN
0,,No LVII
H2N,9 LVIII
H 0 el ,NH
II
0 N.õ--LIX
IL Si NH
II
-N N,,) =
LX
HO IP
NH
LXI
NH
N N
LXII
oH 0 SI
N,11 NH r g I
N
,s NH
ON
I
N
LXIV
CN 9 el NH
rtr I
1\r N
LXV
O N.õ) I
N N
LXVI
0 OEt N N
I
LXVII
NH
N 1\1) N
LX VIII
Cl I
N NH
LXIX
H2N1 el NH
N N
LXX
HN
Si NH
N
LX,XI
HN
= I. NH
J1, 1-,NH
N N
LXXII
/ NH
HN
N
LXX.III
/ NH
CI
HN
N
N
N N
L)C.XIV
/ NH
HN
=N N =
LXXV
/ NH
si CI
HN
401 IC)'`
N
LXXVI
/NH
F
HN
N
LXXVII
N N
NN
LXXVIII
HN
"'XXIX
N-NH
HN
N C)---CNH
N
LYOOC
CI tai NH
N) N
LLXXI
CI a O NH
=
N
NH
LXXXII
CI
1111111" NH
N
N N:Th NH
ISO
NH
HON N
N N
LXXXIV
HN9--0b NH N-"
N r\i-) N N
LXXXV
NH
=&,NNIMP
LXXXVI
NH
0 N,,J
I
N
LXXXVII
9 lel NH
NN
N
LXXXVIII
HO
NH
NH
N N N
LXXXIX
NH
N(1"---NH
XC
N sj N NH
XCI
NH
õ.) s,õ,L N
1\
N
XCII
NNSN
XCIII
NH
NH
N
41111) XCIV
CI
0 NH (NH
N
XCV
CI
SI
N
XCVI
NH
N
NO
N
XCVII
>-IS\ Si NH
0"0 I
N
NH
N
XCVIII
OH
NN N
XCIX
Si NH
LN
>õ N
NH
0"0 N
CI
>,-N.is\ 411 NH
N N
NNS
CII
>,-N,A
NH.
N N
CHI
CI
t\ N L,,,õ NH
CIV
NH
0"O
N
CV
H
NH
N
CVI
H
N \
NH
CVII
H
N
NH
00 N'') .õ2.L
N N
CVIII
H
NH
N N-N\
CIX
H
N \ NH
I ISO
N
CX
>, N ,1s\
NH N
N
0"0 N
CXI
NH
NH
0 ' \o tNN
õN
HN-N
CXII
H
>,Ns\
NH HN-N, d 0 N
I
N
CXHI
NH
NN
CXIV
H
>N.,/s\
NH
tN,,N L.0 CXV
HN
NH
N
Nr N=
CXVI
NN 40 õNH
CXVII
CXVIII
N
N
H
CXIX
=
=NH
C) NCN
I
N
CXX
Os/PN/
/
NH
N N
NN
CXXI
\
N 1\1-NN
CXXII
0 z.-NH N-N N
cxxm zo 40 NH rN-N
I
N
CX.XIV
z ki 0zz.-s=LN
N
NN
CXXV
,0 NH
14" NH NH
y NN
CX.XVI
S-NH".
NH
I
N
CXXVII
,0 NH
N
NN
N "Th NH
CXXVIII
S-NH
41) N N
OH
CXXIX
'LN N
I
N
CXXX
HN
Cl gab 411" NH
N
N
NH
CXXXI
IP NH
N
CXXXII
* NH
CXXXIII
N
* NH NH
N N
CXXXIV
* NH
=IN c,,,0 N N
CXXXV
NI, fel s NH
C)/ \
N C) N N
CXXXVI
N H N
N N
CXXXVII
H
N
CXXXVIII
H
N ;s N
N N
CX.,OCIX
N N
N H
N N
CXL
HO 4111' NH
N (::)'=
N NH
CXL I
1410 NH =
N C)NO
NN
CXLII
=rN ON
NN
CXLIII
CI
NH 0õ0 \SI
`'.1\1=%LN ,_,N1H
CXLIV
Cl WI NH
\) N 0, CXLV
NH
H
1\f%i.N/ 410 õõ.NH
CXLVI
NH
_____________________________ N C)Th N
CXLVII
el N N I.NH
H H
N
N N
CXLVIII
=
H H
N 1\1'=
N N
CXLIX
F3C el NH
N
N NH
CL
ON
NH
0 (:),Th =
N N
CLI
H
NH
o N
N
CLII
H
NH
N
CLIII
NH
HN
tin "N N
JL
CLIV
HN
NH
0" 0 N N
CLV
HN
N NH
N
CLVI
NNH
A, NO
N N
CL VII
F3C., 410 NO
N N =
CLVIII
CI
N N
CLIX
el NH
"-N N) N N
CLX
CI so NH
YN
NN
and CLXI
* NH
N N
CLXII
[0056] According to another embodiment of the invention, compounds having the general structure (Z):
B-C (Z) are provided for treatment of various diseases, disorders, and pathologies.
[0057] The general structure (Z) includes two chemically connected moieties B and C.
The moiety B in the general structure (Z) includes any moiety selected from the following group:
CI 0 CI 0 el SI
0 NH 0 NH n 2,,, m el NH NH
,-, 1.NN
H H H = H
HO lei <0 ei II
.13 40 )`N'.IN
I N "N
(NI\l'i 'I\I-N
H H H H
0Si H el N CI
I
HO NH NH 0. NH N NH
0 -,) L'I\Iy 1\1 '-)- N
1 i. t tNN( N'I\1.) NN. N N -z.V
H H H H
NC
si 1010 cl 4/0 N 410 mr NH CI NH NH CI NH
t.NN) I i II
'N I\I.( '1\r N\ kNN) H H H H
' HN \
Si Cl Cl le NH 0 II N lail NH
"N 'N .-..`-'N1 N
I 1 k.
N NI '22,V N NI la,v NN. N N-H H H H
S 0 Cl \NO =
NH NH = NH NH
\/L
1 V I V jN.N. I V
N NI '2?.. ..N1 NI 12.
H H H H
Cl is S .,, r\I I
F NH NH Cl 4111 NH ''.--NH
N I k N N N N N N N
H H H H
0¨\
F
, 0 .4., 0 0 ,.. too Oil F3c 0 NH NH i 3,,.... NH NH
N N
N
I I I
k NN
N N
H H H H
Cl si ID
F3co IP NH F3C NH '0 NH
N-.N
N N- s'a.V .'N NI .2?_V
H H H
? 110 H2N S NH H2N,11 i NH N NH .
' N 0 H
-N)N.
N N" ''a.V ' Nf\l'( H H H
, HN
NH
\ , NH le NH 161 NH 1 NH
\).
N N N \'' Nk N
tLN I V
'7-H H H H
CI lei )0,, 110 N NH
H H
')'''-'1 N N
N)'N. N N.1/4-= tNLNV
-H H H
HN \
N,Ii .. NH II NH . NH
O N
ON'L.'1 N
1 v tNL,Nk 'N-Nk -1\1 NI 12.
H H H
0 -,-OMe 0 Me0 . NH 0 i 6, F3C N N .. NH
''1\1 H H
il-k t V
N NI ''z. .N N
H H H
H 0 el -N,Q1) 41111 NH lail NH
ii NH
0 -=,,,,-1-, i N NI `'2.. I tN.Nk V ''NV
NI ''a.
HH H
,........., .
H 0 141111 0 '-'--.1 0 0 N II N,cli g ii NH NH
>' NH
II
0 N 0 -,.
'N 0 1 'NJ
tN.N.k 1.NNk , 'NeNk H H H
H 0 I.
,, 0 I. rO
NH NH
NH
II
g ,,.N
r\i I V
N N" ''z. N N NN
- .22.
H H H
Ho 0 OS NH
NH
0 Cr 8 .,--..N 0 NL, ')-N'N1 ' .'N N" '22,V N I\ I -s'z,V
H H H
OC` 0 0 H 1110 o 14111 N, 1 1 -= N -..,ii NHNH
NH
II
II
' 0 .N 0 '---'LN 0 'N
t.NN
1=1 N- `'2. 1\1 N
H H H
H
N
* NH -'-''S'II NH . NH
A.
N NI '22. I I
V . N N N NI "42.NK
H H H
m 0 'S NH 1101 I NH NH
II . NH ...--------S \
\O
---- N
I . N N
11(:/ N HN
-'- ' .. Ni.N.( .
'N N .-H H H
NH
r-NI;S\ NH
'-IN \) 'N 0' b HNõ..- ,..),N
I V NiN.\
H H H
, , HN -N HN\ -\
110 F lei HN
H 0 el -õH
NH NH 1411 NH ..---N
N -"N NY)N1 0 ,..) N N NN N N- "'z.V
H H H H
,and H 9 0>,-N, NH
tNN.
H .
[0058] The moiety C in the structure (Z), above, includes any moiety selected from the following group:
0 0....._,------N9 40 . g,11,.o 140 NH el 0,.õ,-, OH * .L 41 N.' O N
.NH
.40 Nõ
40 N,. .,----) ..NH
r Sc?I.,) 0'-, -__\
, scõ. 01 N.Th 1\1.
rNH rN....---...,,,,OH
rNH
=N) 0 c), ei I\1N. N N.) --_,,NH
cF3 NH
N el N.
So Si L--/- N el 9s-N,_ OI
,F3 Nj.1 N N-4110 9,N
N NOH
NH
Nq 1.1 = I .A\I N
HN-N
el NO 40 1\(c) CNH
rN)C NH
,N
00) N NO0 lei r\i`--) ,and [0059] The compounds and methods of the present invention, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, either when administered alone or in combination with other agents (e.g., chemotherapeutic agents or protein therapeutic agents described below) are useful in treating a variety of disorders, including, but not limited to, for example, myeloproliferative disorders, proliferative diabetic retinopathy and other angiogenic-associated disorders including solid tumors and other types of cancer, eye disease, inflammation, psoriasis, and a viral infection. The kinds of cancer that can be treated include, but are not limited to, an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myelogenous leukemia and chronic myelogenous leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.
[0060] Some examples of the diseases and disorders that can be treated also include ocular neovasculariaztion, infantile haemangiornas; organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psbriasis, Type I diabetes and complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, other blood disorders, asthma, rhinitis, atopic, dermatitits, autoimmune thryroid disorders, ulerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, conditions associated with cytokines, and other autoimmune diseases including glomerulonephritisõ scleroderma, chronic thyroiditis, Graves' disease, autoinunune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g., allergic asthma, atopic dermatitis, or allergic rhinitis), chronic active hepatitis, myasthenia graivs, multiple scleroiss, inflammatory bowel disease, graft vs host disease, neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral scelerosis, Huntington's disease, cerebral ischemia, or neurodegenerative disease caused by traumatic injury, strike, gluatamate neurtoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hyoxia, and platelet aggregation.
[00611 Examples of some additional diseases and disorders that can be treated also include cell mediated hypersensitivity (allergic contact dermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g., systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriatic arthritis), viral diseases (Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, HTLVI, Vaicella-Zoster Virus, Human Papilloma Virus), food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.
In one embodiment, the disorder that can be treated is a myeloproliferative disorder. In one embodiment, the myeloproliferative disorder arises due to mutations in a kinase. In one embodiment, the myeloproliferative disorder arises due to gain-of-function of a JAK
family kinase pathway. In one embodiment, the myeloproliferative disorder arises as a result of gene or protein fusions due to gain-of-function of a JAK family kinase pathway.
[0062] Embodiments of the present invention also provide articles of manufacture that can include a packaging material and a pharmaceutical composition contained within the packaging material. The packaginit material can comprise a label which indicates that the pharmaceutical composition can be used for treatment of one or more disorders identified above.
[0063) The pharmaceutical composition can include a compound according to the present invention. In addition to a compound of the present invention, the pharmaceutical may also contain other therapeutic agents, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques known in the art of pharmaceutical formulation.
[00641 Thus, in one embodiment, the invention provides a pharmaceutical composition including a therapeutic agent and a compound of the invention. The compound is present in a concentration effective to treat, for example, cancer or to treat another disease or disorder described above.
10065] The compounds of the invention may be formulated into therapeutic compositions as natural or salt forms. Pharmaceutically acceptable non-toxic salts include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylarnino-ethanol, histidine, procaine, and the like. Such salts may also be formed as acid addition salts with any free cationic groups and will generally be formed with inorganic acids such as, for example, hydrochloric, sulfuric, or phosphoric acids, or organic acids such as acetic, citric, p-toluenesulfonic, methanesulfonic acid, oxalic, tartaric, mandelic, and the like.
100661 Salts of the invention can include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the invention can also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p-toluenesulfonic acid, acetic acid, methanesulfonic acid and the like.
Additional excipients which are contemplated for use in the practice of the present invention are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. >all and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, MD (1989). In addition, polymorphs of the invention compounds are included in the present invention.
[00671 Pharmaceutical compositions of the invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders;
sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray;
topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally.
[00681 In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens).
[0069] The pharmaceutical compositions for the administration of the compounds of this embodiment, either alone or in combination with other therapeutic agents, may conveniently be presented in dosage unit fouli and may be prepared by any of the methods well known in the art of pharmacy. All methods include bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by unifolinly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
[0070] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical- compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release.
[0071] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[0072] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Also useful as a solubilizer is polyethylene glycol, for example.
The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0073] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
[0074] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
[0075] Syrups and elixirs may be fonnulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
[0076] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable diluent or solvent or cosolvent or complexing agent or dispersing agent or excipient or combination thereof, for example 1,3-butanediol, polyethylene glycols, polypropylene glycols, ethanol or other alcohols, povidones, various brands of TWEEN surfactant, sodium dodecyl sulfate, sodium deoxycholate, dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, and excipients such as inorganic salts (e.g., sodium chloride), buffering agents (e.g., sodium citrate, sodium phosphate), and sugars (e.g., saccharose and dextrose). Among the acceptable vehicles and solvents that may be employed are water, dextrose solutions, Ringer's solutions and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[0077] Depending on the condition being treated, these pharmaceutical compositions may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences"
(Mack Publishing Co, Easton Pa.). Suitable routes may, for example, include oral or transmucosal administration; as well as parenteral delivery, including intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration. For injection, the phainiaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[0078] The compounds of the present invention may also be administered in the faun of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
[0079] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles).
[0080] In one embodiment, the invention compounds are administered in combination with an anti-inflammatory agent, antihistamines, chemotherapeutic agent, immunomodulator, therapeutic antibody or a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor, to a subject in need of such treatment. While not wanting to be limiting, chemotherapeutic agents include antimetabolites, such as methotrexate, DNA cross-linking agents, such as cisplatinicarboplatin; alkylating agents, such as canbusil; topoisomerase I
inhibitors such as dactinomicin; microtubule inhibitors such as taxol (paclitaxol), and the like.
Other chemotherapeutic agents include, for example, a vinca alkaloid, mitomycin-type antibiotic, bleomycin-type antibiotic, antifolate, colchicine, demecoline, etoposide, taxane, anthracycline antibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin, idarubicin, mithoxanthrone, 4-dimethoxy-daunomycin, 11-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate, adriamycin-14-octanoate, adriamycin-14-naphthaleneacetate, amsacrine, carmustine, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topetecan, oxalaplatin, chlorambucil, methtrexate, lomustine, thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, or mechlorethamine. While not wanting to be limiting, therapeutic antibodies include antibodies directed against the HER2 protein, such as trastuzumab; antibodies directed against growth factors or growth factor receptors, such as bevacizumab, which targets vascular endothelial growth factor, and OSI-774, which targets epidermal growth factor; antibodies targeting integrin receptors, such as Vitaxin (also known as MEDI-522), and the like. Classes of anticancer agents suitable for use in compositions and methods of the present invention include, but are not limited to: 1) alkaloids, including, microtubule inhibitors (e.g., Vincristine, Vinblastine, and Vindesine, etc.), microtubule stabilizers (e.g., Paclitaxel [Taxol], and Docetaxel, Taxotere, etc.), and chromatin function inhibitors, including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide [VP-16], and Teniposide [VM-26], etc.), and agents that target topoisomerase I
(e.g., Camptothecin and Isirinotecan [CPT-11], etc.); 2) covalent DNA-binding agents [alkylating agents], including, nitrogen mustards (e.g., Mechlorethamine, Chlorambucil, Cyclophosphamide, Ifosphamide, and Busulfan [Myleran], etc.), nitrosoureas (e.g., Cartnustine, Lomustine, and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine, Thiotepa, and Mitocycin, etc.); 3) noncovalent DNA-binding agents [antitumor antibiotics], including, nucleic acid inhibitors (e.g., Dactinomycin [Actinomycin D], etc.), anthracyclines (e.g., Daunorubicin [Daunomycin, and Cerubidine], Doxorubicin [Adriamycin], and Idarubicin [Idamycin], etc.), anthracenediones (e.g., anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicamycin (Mithramycin), etc.; 4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex, and Mexate, etc.), purine antimetabolites (e.g., 6-Mercaptopurine [6-MP, Purinethol], 6-Thioguanine [6-TG], Azathioprine, Acyclovir, Ganciclovir, Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine [CdA], and 2'-Deoxycofonnycin [Pentostatin], etc.), pyrimidine antagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosine arabinosides (e.g., Cytosar [ara-C]
and Fludarabine, etc.); 5) enzymes, including, L-asparaginase; 6) hoiniones, including, glucocorticoids, such as, antiestrogens (e.g., Tamoxifen, etc.), nonsteroidal antiandrogens (e.g., Flutamide, etc.), and aromatase inhibitors (e.g., anastrozole [Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin and Carboplatin, etc.); 8) monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides, etc.; 9) biological response modifiers (e.g., interferons [e.g., IFN-.alpha., etc.] and interleukins [e.g., IL-2, etc.], etc.); 10) adoptive immunotherapy; 11) hematopoietic growth factors; 12) agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastases (e.g., Batimistat, etc.); and 17) inhibitors of angiogenesis.
[00811 The phaimaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. Examples of other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 and gp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof.
[0082] Other agents that may be administered in combination with invention compounds include protein thera'peutic agents such as cytokines, immunomodulatory agents and antibodies. As used herein the term "cytokine" encompasses chemokines, interleukins, lymphokines, monokines, colony stimulating factors, and receptor associated proteins, and functional fragments thereof. As used herein, the term "functional fragment"
refers to a polypeptide or peptide which possesses biological function or activity that is identified through a defined functional assay.
[0083] The cytokines include endothelial monocyte activating pol)peptide II
(EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF
(M-CSF), IL-1, IL-2, 1L-3, IL-4, IL-5, IL-6, IL-12, and 1L-13, interferons, and the like and which is associated with a particular biologic, morphologic, or phenotypic alteration in a cell or cell mechanism.
[0084] When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one having ordinary skill in the art.
[0085] In the treatment or prevention of conditions which involve cellular proliferation, an appropriate dosage level can generally be between about 0.01 and about 1000 mg per 1 kg of patient body weight per day which can be administered in single or multiple doses. For example, the dosage level can be between about 0.01 and about 250 mg/kg per day; more narrowly, between about 0.5 and about 100 mg/kg per day. A suitable dosage level can be between about 0.01 and about 250 mg/kg per day, between about 0.05 and about 100 mg/kg per day, or between about 0.1 and about 50 mg/kg per day, or about 1.0 mg/kg per day. For example, within this range the dosage can be between about 0.05 and about 0.5 mg/kg per day, or between about 0.5 and about 5 mg/kg per day, or between about 5 and about 50 mg/kg per day. For oral administration, the compositions can be provided in the foim of tablets containing between about 1.0 and about 1,000 mg of the active ingredient, for example, about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1,000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
The compounds can be administered on a regimen of 1 to 4 times per day, such as once or twice per day. There may be a period of no administration followed by another regimen of administration.
[0086] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
[0087] Compounds of the present invention can be used, alone or in combination with an effective amount of a therapeutic antibody (or therapeutic fragment thereof), a chemotherapeutic or an immunotoxic agent, for treatment of tumors.
Illustrative examples of chemotherapeutic agents that can be used for this purpose include doxorubicin, docetaxel, or taxol. It should be further understood that the invention includes combination therapy including a compound of the invention, including but not limited to vasculostatic agents, such as tyrosine, serine or threonine kinase inhibitors, and any chemotherapeutic agent or therapeutic antibody.
C. Examples [0088] The following examples are provided to further illustrate the advantages and features of the present invention, but are not intended to limit the scope of the invention.
EXAMPLE 1. General Methods [0089] All experiments were performed under anhydrous conditions (i.e. dry solvents) in an atmosphere of argon, except where stated, using oven-dried apparatus and employing standard techniques in handling air-sensitive materials. Aqueous solutions of sodium bicarbonate (NaHCO3) and sodium chloride (brine) were saturated. Analytical thin layer chromatography (TLC) was carried out on Merck Kieselgel 60 F254 plates with visualization by ultraviolet and/or anisaldehyde, potassium permanganate or phosphomolybdic acid dips.
Reverse-phase HPLC chromatography was carried out on Gilson 215 liquid handler equipped with Waters SyinmetiyShieldTM RP18 7 m (40 x 100mm) Prep-Pak cartridge. Mobile phase consisted of standard acetonitrile (ACN) and DI Water, each with 0.1% TFA
added.
Purification was carried out at a flow rate of 40mL/ min. NMR spectra: 1H
Nuclear magnetic resonance spectra were recorded at 500 MHz. Data are presented as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn =
quintet, dd = doublet of =
doublets, m = multiplet, br s = broad singlet), coupling constant (J/Hz) and integration.
Coupling constants were taken directly from the spectra and are uncorrected.
Low resolution mass spectra: Electrospray (ES+) ionization was used. The protonated parent ion (M+H) or fragment of highest mass is quoted. Analytical gradient consisted of 10% ACN
in water ramping up to 100% ACN over 5 min unless otherwise stated.
EXAMPLE 2. N4-(4-Methoxy-phenyI)-pyrimidine-2,4-diamine (Intermediate 1) NH
N
[0090] A mixture of 4-ch1oro-pyrimidin-2-ylamine (0.30 g, 2.3 mmol) and 4-methoxy-phenylamine (0.30 g, 2.4 mmol) were suspended in acetic acid (10 mL) and heated at 100 C
for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7 with 7M
of NaOH solution. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered.
The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (hexane to Et0Ac) to afford the title intermediate 1 (0.23 g, 45%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 3.69 (s, 3H), 5.84 (d, J=
5.8 Hz, 1H), 6.79 (d, J= 9.1 Hz, 2H), 7.63 (d, J= 9.1 Hz, 2H), 7.78 (d, J= 5.8 Hz, 1H), 8.65 (s, 1H);
MS (ESI+): m/z 217 (M+H)+.
EXAMPLE 3. M-(4-Methoxy-pheny1)-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound I) NH
410 (341..D
N
[0091] To synthesize compound I, intermediate 1 described above and intermediate 2 were used. Inteiniediate 2, 142-(4-bromo-phenoxy)-ethyl]Tyrrolidine, shown below is available commercially, and was used as received.
Br =
(2) [0092] A suspension of intermediate 1 (74 mg, 0.34 mmol), intermediate 2 (0.10 g, 0.37 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.05 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3/1; 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 mm. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC to afford the title compound I (20 mg of TFA salt, 11%) as a brown solid. 1H NMR (500 MHz, DMSO-d6): 1.80-1.95 (m, 2H), 1.95-2.10 (m, 2H), 3.05-3.20 (m, 2H), 3.55-3.65 (m, 4H), 3.77 (s, 3H), 4.29 (t, J= 4.9 Hz, 2H), 6.30 (d, J= 6.8 Hz, 1H), 6.96 (d, J=
8.3 Hz, 2H), 6.98 (d, J= 8.3 Hz, 2H), 7.41 (d, J= 8.8 Hz, 2H), 7.55 (d, J= 8.8 Hz, 2H), 7.89 (d, J= 6.2 Hz, 1H), 9.87 (br s, 1H), 10.22 (br s, 1H), 10.44 (br s, 1H); MS (ESI+): nilz 406 (M+H)4.
EXAMPLE 4. 4-[4-(4-Methoxy-phenylamino)-pyrimidin-2-0aminol-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (Compound II) NH
N
j, OH
II
[0093] To synthesize compound II, intermediate 1 described above and intermediate 3 were used. Intermediate 3, 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, the formula of which is shown below, was synthesized from 4-bromophenylsulfonylchloride and 2-aminoethylpyrrolidine, using commonly known synthetic techniques.
-N'Nr'D
Br [0094] A suspension of intermediate 1 described above (70 mg, 0.32 mmol), intermediate 3 (0.12 g, 0.36 mmol), Pd(OAc)2 (5 mg, 0.022 mmol), Xantphos (26 mg, 0.05 mmol) and potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3/1; 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC to afford the title compound II (0.16 g of TFA salt, 85%) as a white solid. 1H
NMR (500 MHz, DMSO-d6): 1.80-1.95 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.23 (q, J=
5.8 Hz, 2H), 3.50-3.60 (m, 2H), 3.79 (s, 3H), 6.41 (d, J= 6.8 Hz, 1H), 6.99 (d, J= 8.9 Hz, 2H), 7.43 (d, J= 8.9 Hz, 2H), 7.71 (d, J= 8.6 Hz, 2H), 7.85-7.95 (m, 2H), 7.96 (t, J=
6.1 Hz, 1H), 8.02 (d, J= 6.2 Hz, 1H), 9.64 (br s, 1H), 10.21 (br s, 1H), 10.71 (br s, 1H);
MS (ESI+): nilz 469 (M+H)+.
EXAMPLE 5. 4-14-(4-Hydroxy-phenylamino)-pyrimidin-2-ylaminol-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (Compound III) HO is NH
II JOH
Ill [0095] To a solution of compound II described above (50 mg, 0.09 mmol) in DCM
(6 mL) at room temperature was added I3Br3 (0.1 mL) and the mixture stirred at room temperature for 2.5 h. The reaction was quenched with saturated NaHCO3 solution until the pH-7 and the mixture extracted with Et0Ac (30 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the resulting solid re-dissolved in minimum of Et0Ac. Hexane was added until solid crushed out and the title compound III was filtered as a white solid (25 mg, 64%) without further purification. 1H NMR (500 MHz, DMSO-d6): 1.55-1.65 (m, 4H), 2.30-2.40 (m, 4H), 2.43 (t, J= 7.0 Hz, 2H), 2.82 (t, J= 6.6 Hz, 2H), 6.20 (d, J= 5.8 Hz, 1H), 6.70 (d, J=
8.8 Hz, 2H), 7.40 (d, J= 8.6 Hz, 2H), 7.64 (d, J= 8.8 Hz, 2H), 7.92 (d, J= 8.4 Hz, 2H), 8.03 (d, J- 5.5 Hz, 1H), 8.93 (s, 1H), 9.08 (br s, 1H), 9.70 (s, 1H); MS (ESI+): in/z 455 (M+H)+.
EXAMPLE 6. 4-(4-Chloro-pyrimidin-2-ylamino)-N-(2-pyrrolidin-l-yl-ethyl)-benzenesulfonamide (Intermediate 4) ci N
.,1õ. 0 H
=N N
[0096] A mixture of 4-chloro-pyrimidin-2-ylamine (1.0 g, 7.8 mmol), above-described intermediate 3 (2.6 g, 7.8 mmol), Pd(OAc)2 (90 mg, 0.40 mmol), Xantphos (0.50 g, 0.86 mmol) and potassium tert-butoxide (2.2 g, 20 mmol) were suspended in dioxane (30 mL) and heated at reflux under the argon atmosphere for 16 h. The mixture was poured into water (30 mL) and extracted with Et0Ac (60 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 25% Me0H/DCM) to afford the title intermediate 4 (0.15 g, 5%) as a brown solid. MS (ESI+): inlz 382 (M+H)+.
EXAMPLE 7. 4-[4-(3-Methoxy-phenylamino)-pyrimidin-2-ylaminol-N-(2-pyrrolidin-1-yl-ethy1)-benzenesulfonamide (Compound IV) NH
b.
N
OH
N
Iv [0097] A mixture of the above described intermediate 4 (0.10 g, 0.26 mmol) and 3-methoxy-phenylamine (0.05 mL, 0.45 mmol) were suspended in acetic acid (6 mL) and heated at 100 C for 1.5 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound IV (55 mg of TFA salt, 36%) as a white solid. 1H NMR
(500 MHz, DMSO-d6): 1.80-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.24 (q, J=
6.0 Hz, 2H), 3.50-3.60 (m, 2H), 3.73 (s, 3H), 6.40 (d, J= 6.3 Hz, 1H), 6.68 (d, J= 7.3 Hz, 1H), 7.18 (d, J= 8.2 Hz, 1H), 7.26 (t, J= 8.0 Hz, 1H), 7.30 (s, 1H), 7.72 (d, J= 8.9 Hz, 2H), 7.91 (t, J-6.1 Hz, 1H), 7.95 (d, J= 8.7 Hz, 2H), 8.10 (d, J= 6.2 Hz, 1H), 9.59 (br s, 1H), 9.87 (br s, 1H), 10.38 (br s, 1H); MS (ESI+): m/z 469 (M+H)+.
EXAMPLE 8. 4-[443-Hydroxy-phenylamino)-pyrimidin-2-ylaminol-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (Compound V) HO NH
N N
NN J
H
V
[0098] To a solution of the above-described compound IV (30 mg, 0.05 mmol) in DCM (6 mL) at room temperature was added BBr3 (0.1 mL) and the mixture stirred at room temperature for 2.5 h. The reaction was quenched with saturated NaHCO3 solution until the pH-7 and the mixture extracted with Et0Ac (30 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by HPLC to afford the title compound V (13 mg of TFA salt, 46%) as an off white solid. 1H NMR (500 MHz, DMSO-d6): 1.80-1.90 (m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.20-3.30 (in, 2H), 6.39 (d, J= 6.3 Hz, 1H), 6.53 (d, J= 7.2 Hz, 1H), 7.01 (d, J
= 9.2 Hz, 1H), 7.09 (s, 1H), 7.14 (t, J= 8.1 Hz, 1H), 7.73 (d, J= 8.8 Hz, 2H), 7.90 (t, J= 6.2 Hz, 1H), 7.97 (d, J= 8.8 Hz, 2H), 8.08 (d, J= 6.4 Hz, 1H), 9.48 (br s, 1H), 9.57 (br s, 1H), 9.86 (br s, 1H), 10.41 (br s, 1H); MS (ESI+): m/z 455 (M+H)+.
EXAMPLE 9. Benzo[1,31dioxo1-5-y1-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 5) <0 Ai I
'NN CI
[0099] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5-bromo-benzo[1,3]dioxole (0.45 g, 2.2 mmol), Pd(OAc)2 (30 mg, 0.13 mmol), Xantphos (0.15 g, 0.26 mmol) and potassium tert-butoxide (0.45 g, 4.0 mmol) were suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 16 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated ill vacuo. The residue was purified by flash chromatography on silica gel (hexane to 50% Et0Ac/hexane) to afford the title intermediate 5 (0.10 g, 18%) as a white solid. MS (ESI+): m/z 264 (M+H) .
EXAMPLE 10. /V4-Senzo[1,31dioxo1-5-y1-5-methyl-N2-P1-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound VI) <0 N 40:1 C)Nit.D
N N
VI
[0100[ To synthesize compound VI, intermediate 5 described above and inteunediate 6 were used. Intermediate 6, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine, the fonnula of which is shown below, was synthesized in two steps, first by alkylation of 4-nitrophenol using 2-chloroethylpyrrolidine, followed by reduction to yield the aniline derivative.
[0101] Commonly known synthetic techniques were used to synthesize intermediate 6. A
mixture of the above-described intermediate 5 (90 mg, 0.34 mmol), intermediate 6 (95 mg, 0.46 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), Xantphos (30 mg, 0.05 mmol) and cesium carbonate (0.30 g, 0.9 mmol) were suspended in dioxane (10 mL) and heated at reflux under the argon atmosphere for 20 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo.
The residue was purified by HPLC to afford the title compound VI (40 mg of TFA
salt, 21%) as a brown solid. 111 NMR (500 MHz, DMSO-d6): 1.85-1.95 (m, 2H), 1.95-2.05 (m, 2H), 2.13 (s, 3H), 3.10-3.20 (m, 2H), 4.26 (t, J= 5.0 Hz, 2H), 6.07 (s, 2H), 6.90-7.00 (m, 4H), 7.19 (s, 1H), 7.37 (d, J= 9.0 Hz, 2H), 7.84 (s, 1H), 9.60 (hr s, 1H), 9.89 (br s, 1H), 10.32 (hr s, 1H); MS (ESI+): nz/z 434 (M+H)+.
EXAMPLE 11. (4-Chloro-3-methoxy-pheiry1)-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 7) I
CI
[0102] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol), brorno-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% Et0Ac/hexane) to afford the title intermediate 7 (0.55 g, 55%) as a yellow solid. ill NMR (500 MHz, DMSO-d6): 2.18 (s, 3H), 3.85 (s, 3H), 7.35 (dd, J= 8.6 Hz, J= 2.3 Hz, 1H), 7.39 (d, J= 8.7 Hz, 1H), 7.56 (d, J=
2.3 Hz, 1H), 8.09 (d, J= 0.9 Hz, 1H), 8.91 (s, 1H); MS (ESI+): m/z 284 (M+H) .
EXAMPLE 12. (4-Chloro-3-rnethoxy-pheny1)-(2-ehloro-5-methyl-pyrimidin-4-y1)-methyl-amine (Intermediate 8) CI
N
NCI
[0103] A suspension of intermediate 7 (0.50 g, 1.8 mmol) and sodium hydride (60% in mineral oil, 0.15 g, 3.8 mmol) in THF (10 mL) was stirred under the argon atmosphere at 0 C for 5 mm. Methyl iodide (0.15 mL, 2.4 mmol) was syringed at the same temperature to the above mixture. The resulting solution was stirred from 0 C to room temperature over 15 min and further stirred at room temperature for additional 17 h. The reaction was quenched with water (10 mL) and then extracted with Et0Ac (30 mL). The organic layer was separated and washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexane to 20%
Et0Ac/hexane) to afford the title intermediate 8 (0.20 g, 38%) as a white solid. MS (ESI+):
nilz 298 (M+H)+.
EXAMPLE 13. N2-(4-(2-(pyrrolidin-1-ybethoxy)pheny1)-N4-(4-chloro-3-methoxvphenyll-N4,5-dimethvlpyrimidine-2,4-diamine (Compound VII) Cl ON
N N
VII
[0104] A mixture of intermediate 8 (0.15 g, 0.49 mmol) and intermediate 6 (0.15 g, 0.73 mmol), each of which intemiediates is described above, were suspended in acetic acid (8 mL) and heated at 100 C for 17 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH solution. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound VII (0.14 g of TFA salt, 49%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 1.85-1.95 (m, 2H), 2.00-2.10 (m, 2H), 3.08-3.18 (m, 2H), 3.46 (s, 3H), 3.55-3.65 (m, 4H), 3.85 (s, 3H), 4.27 (t, J= 5.0 Hz, 2H), 6.86 (d, J= 7.4 Hz, 1H), 7.01 (d, J= 9.0 Hz, 2H), 7.15 (s, 1H), 7.46 (d, J= 8.4 Hz, 1H), 7.58 (d, J= 8.9 Hz, 2H), 7.83 (s, 1H), 9.85 (br s, 1H), 10.04 (br s, 1H), 10.32 (br s, 1H); MS
(ESI+): ni/z 468 (M+H)+.
EXAMPLE 14. t-5-meth rhnidiu--di1oro- hen 1 -amine (Intermediate 9) CI
NH
N
CI
[0105] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 1-bromo-4-chloro-benzene (0.60 g, 3.1 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% Et0Aciltexane) to afford the title intermediate 9 (0.15 g, 28%) as a pale yellow solid. MS (ESI+): nilz 254 (M+H)+.
EXAMPLE 15. /V4-(4-Chloro-pheny1)-5-methyl-N244-(2-pyrrolidin4-yl-ethoxy)-- phenyn-pyrimidine-2,4-diamine (Compound VIII) CI, NH
N (21NLD
N N
VIII
[0106] A mixture of the above-described intermediates 9 (0.15 g, 0.60 mmol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 mL) and heated at 100 C for 6 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH
solution. The resulting brown solid was filtered and further purified by HPLC
to afford the title compound VIII (38 mg of TFA salt, 12%) as a brown oil. 1H NMR (500 MHz, d6): 1.80-1.95 (m, 2H), 2.00-2.10 (m, 2H), 2.15 (s, 3H), 3.10-3.20 (m, 2H), 3.55-3.65 (m, 4H), 3.77 (s, 3H), 4.28 (t, J= 5.0 Hz, 2H), 6.95 (d, J= 9.0 Hz, 2H), 7.38 (d, J= 8.9 Hz, 2H), 7.42 (d, J= 8.9 Hz, 2H), 7.62 (d, J= 8.8 Hz, 2H), 7.90 (s, 1H), 9.48 (br s, 1H), 9.84 (br s, 1H), 10.10 (br s, 1H); MS (ESI+): n2/z 424 (M+H)+.
EXAMPLE 16. 244-Amino-phenoxy)-ethanol (Intermediate 10) [0107] A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in Me0H (30 mL) was flushed with argon and then charged with Pd/C (10% by wt). The mixture was evacuated under house vacuum and then refilled with hydrogen from hydrogen balloon. The cycle was repeated again and the mixture stirred at room temperature for 2 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo to furnish the title intermediate 10 (1.8 g, 99%) as a brown solid.
MS (ESI+): ni/z 154 (M+H)+.
EXAMPLE 17. 2-14-1-4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylaminol-phenoxyl-ethanol (Compound IX) mr NH
'NN 410 C'OH
N
IX
[0108] A suspension of the above described intermediates 7 (50 mg, 0.17 mmol), 10 (40 mg, 0.26 mmol), Pd2(dba)2 (8 mg, 0.01 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 mm. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM.
The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexane to Et0Ac) to afford the title compound IX (14 mg, 21%) as a light brown solid. 11-1 NMR (500 MHz, DMSO-d6): 2.10 (s, 3H), 3.69 (t, J= 5.3 Hz, 2H), 3.75 (s, 3H), 3.92 (t, J=
5.1 Hz, 2H), 4.83 (t, J= 5.6 Hz, 1H), 6.78 (d, J= 9.0 Hz, 2H), 7.29 (d, J= 8.5 Hz, 1H), 7.43 (dd, J= 8.6 Hz, J= 2.2 Hz, 1H), 7.48 (d, J= 2.3 Hz, 1H), 7.52 (d, J= 9.0 Hz, 2H), 7.88 (s, 1H), 8.31 (s, 1H), 8.80 (s, 1H); MS (ESI+): 771/Z 401 (M+H)+.
EXAMPLE 18. 5-Methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Intermediate 11) 1401 ()NO
\ NN
[0109] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.13 g, 0.87 mmol) and the above described intermediate 6 (0.30 g, 1.5 mmol) were suspended in acetic acid (8 mL) and heated at 100 C for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH solution. The resulting solid was filtered (30 mg) and washed with ether. The filtrate was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated to afford the additional solid (0.2 g), which were combined with the first batch and afforded the title intermediate 11 (0.23 g, 85%) as a light brown solid. Ili NMR (500 MHz, DMSO-d6): 1.65-1.70 (m, 4H), 1.89 (s, 3H), 2.74 (t, J= 6.0 Hz, 2H), 3.98 (t, J= 6.1 Hz, 2H), 6.30 (s, 2H), 6.78 (d, J= 9.1 Hz, 2H), 7.62 (d, J= 9.1 Hz, 2H), 7.64 (s, 1H), 8.50 (s, 1H); MS (ESI+): m/z 314 (M+H)+.
EXAMPLE 19. 5-Methyl-NI-phenyl-N2-14-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound X) () N
X
[0110] A suspension of the above-described intermediate 11 (25 mg, 0.08 mmol), bromobenzene (0.05 mL, 0.50 imnol), Pd2(dba)2 (5 mg, 0.006 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate (70 mg, 0.21 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% Me0H/DCM) to afford the title compound X (10 mg, 32%) as alight brown solid. 1H NMR (500 MHz, DMSO-d6): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.48-2.58 (m, 4H), 2.75-2.82 (m, 2H), 4.00 (t, J= 5.9 Hz, 2H), 6.77 (d, J= 9.0 Hz, 2H), 7.04 (t, J= 7.3 Hz, 1H), 7.32 (t, J= 7.9 Hz, 2H), 7.54 (d, J= 9.0 Hz, 2H), 7.71 (d, J=
7.8 Hz, 2H), 7.84 (s, 1H), 8.20 (s, 1H), 8.76 (s, 1H); MS (ESI+): m/z 390 (M+H)+.
EXAMPLE 20. (4-Chloro-3-fluoro-pheny1)-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 12) CI, NH
N
I
CI
[0111] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mrnol), 4-Bromo-1-chloro-2-fluoro-benzene (1.0 g, 4.8 mmol), Pd2(dba)3 (0.16 g, 0.17 mmol), Xantphos (0.20 g, 0.34 mmol) and cesium carbonate (2.3 g, 7.0 mmol) were suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 15 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% Et0Ac/hexane) to afford the title intermediate 12 (0.75 g, 80%) as an off white solid. MS (ESI+): m/z 272 (M+H)+.
EXAMPLE 21. /V4-(4-Chloro-3-fluoro-phenyl)-5-methyl- N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound XI) CI
N H
N
I
N
XI
[0112] A mixture of the above-described inten-nediates 12 (0.20 g, 0.74 mmol) and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 mL) and heated at 100 C for 6 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH
solution. The resulting solution was extracted with EtOAc (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 30% Me0H/DCM) to afford the title compound XI (90 mg, 28%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 1.65-1.71 (m, 4H), 2.10 (s, 3H), 2.45-2.55 (m, 4H), 2.77 (t, J= 6.0 Hz, 2H), 4.01 (t, J= 6.0 Hz, 2H), 6.82 (d, J= 9.0 Hz, 2H), 7.44 (t, J=
8.8 Hz, 1H), 7.50 (d, J= 9.0 Hz, 2H), 7.55 (dd, J= 8.9 Hz, J= 2.0 Hz, 1H), 7.91 (s, 1H), 8.07 (dd, J= 12.5 Hz, J= 2.0 Hz, 1H), 8.43 (s, 1H), 8.90 (s, 1H); MS (ESI+): m/z 442 (M+H)+.
EXAMPLE 22. N4-(4-Chloro-3-methoxy-phenyI)-5-methyl-N2-(4-morpholin-4-ylmethyl-phenyl)-pyrimidine-2,4-diamine (Compound XII) CI
t4111 NO
N N ) XII
[0113] A suspension of the above-described intermediate 7 (50 mg, 0.17 mmol), 4-morpholin-4-ylmethyl-phenylamine (50 mg, 0.26 mmol), Pd2(dba)2 (8 mg, 0.009 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC to afford the title compound XII (40 mg of TFA salt, 43%) as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6): 2.16 (s, 311), 3.05-3.15 (m, 2H), 3.10-3.20 (m, 2H), 3.60-3.70 (m, 2H), 3.90-4.00 (m, 2H), 4.28 (s, 2H), 4.01 (t, J= 6.0 Hz, 2H), 7.25-7.35 (m, 3H), 7.35-7.41 (m, 2H), 7.65 (d, J.= 8.3 Hz, 211), 7.98 (s, 1H), 9.10 (br s, 1H), 9.86 (br s, 1H), 9.95 (br s, 1H); MS (ESI+): tn/z 440 (M+H)+.
EXAMPLE 23. Benzoibithiophen-5-y142-chloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 13) NH
N
I
N CI
[0114] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 5-bromo-benzo[b]thiophene (0.6 g, 2.8 nn-nol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% Et0Ac/hexane) to afford the title interinediate 13 (0.23 g, 40%) as a white solid. MS (ESI+): in/z 276 (M+H)+.
EXAMPLE 24. N4-Benzo[b]thiophen-5-y1-5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyi]-pyrimidine-2,4-diamine (Compound XIII) NH
LI
= N
N N
XIII
[0115] A mixture of the above-described intermediates 13 (0.23 g, 0.83 mmol) and 6 (0.35 g, 1.7 mmol) were suspended in acetic acid (8 mL) and heated at 100 C for 1 d. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure.
The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH
solution.
The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated.
The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 15% Me0H/DCM) to afford the title compound XIII (0.13 g, 35%) as a white solid. Ill NMR (500 MHz, DMSO-d6): 1.65-1.75 (m, 4H), 2.12 (s, 3H), 2.50-2.62 (m, 4H), 2.75-2.85 (in, 2H), 3.99 (t, J= 5.9 Hz, 2H), 6.70 (d, J= 9.0 Hz, 2H), 7.36 (d, J- 5.4 Hz, 1H), 7.51 (d, J= 9.1 Hz, 2H), 7.61 (dd, J= 8.7 Hz, J= 2.0 Hz, 1H), 7.74 (d, J
5.4 Hz, 1H), 7.85 (d, J- 0.8 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 8.29 (d, J = 1.7 Hz, 1H), 8.34 (s, 1H), 8.76 (s, 1H); MS (ESI+): in/z 446 (M+H)+.
EXAMPLE 25. Benz [b] thiophen-3-y1-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 14) NH
[0116] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 3-bromo-benzo[b]thiophene (0.6 g, 2.8 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) were suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 30% Et0Ac/hexane) to afford the title intermediate 14 (65 mg, 11%) as a yellow solid. MS (ESI+): m/z 276 (M+H)+.
EXAMPLE 26. NI-Benzo[b]thiophen-3-y1-5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound XIV) =
NH
N
XIV
[0117] A mixture of the above-described intermediates 14 (50 mg, 0.18 mmol) and 6 (0.10 g, 0.48 mmol) was suspended in acetic acid (8 mL) and heated at 100 C for 15 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (10 mL) and neutralized to pH-7 with 7M of NaOH
solution. The resulting solution was extracted with Et0Ac (20 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 15% Me0H/DCM) to afford the title compound XIV (10 mg, 13%) as an off white solid. IHNMR (500 MHz, DMSO-d6): 1.70-1.80 (in, 4H), 2.19 (s, 3H), 2.65-2.80 (in, 4H), 2.85-3.00 (in, 2H), 3.98-4.03 (in, 2H), 6.63 (d, J= 8.8 Hz, 2H), 7.37 (d, J¨ 8.6 Hz, 2H), 7.38-7.45 (in, 2H), 7.79-7.83 (in, 1H), 7.87 (s, 1H), 7.90-8.03 (in, 1H), 8.33 (s, 1H), 8.78 (s, 1H); MS (ESI+): in/z 446 (M+H)+.
EXAMPLE 27. (2-Chloro-5-methyl-pyrimidin-4-y1)-(3-ehloro-phenyl)-amine (Intermediate 151 CI NH
N
CI
[0118] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), 1-bromo-3-chloro-benzene (0.60 g, 3.1 mmol), Pd2(dba)3 (95 mg, 0.10 mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane to 40% Et0Ac/hexane) to afford the title intermediate 15 (0.30 g, 56%) as a pale yellow solid. MS (ESI+): nz/z 254 (M+H)+.
EXAMPLE 28. N4-(3-Chloro-phenyl)-5-methyl-N2-14-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Compound XV) CI NH
NN
XV
[01191 A
mixture of the above-described inteiluediates 15 (0.15 g, 0.59 mmol) and 6 (0.25 g, 1.2 mmol) was suspended in acetic acid (8 mL) and heated at 100 C for 21 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (15 mL) and neutralized to pH-7 with 7M of NaOH
solution. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 10% Me0H/DCM) to afford the title compound XV (60 mg, 24%) as a white solid. 1H NMR (500 MHz, DMSO-d6): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.50-2.60 (m, 4H), 2.78-2.83 (m, 2H), 4.01 (t, J= 5.9 Hz, 2H), 6.81 (d, J= 9.1 Hz, 2H), 7.05-7.08 (m, 1H), 7.32 (t, J= 8.1 Hz, 1H), 7.52 (d, J.= 9.0 Hz, 2H), 7.71 (d, J 8.3 Hz, 1H), 7.85 (t, J= 2.1 Hz, 1H), 7.89 (d, J= 0.7 Hz, 1H), 8.33 (s, 1H), 8.86 (s, 1H); MS (ESI+): mlz 424 (M+H)+.
EXAMPLE 29. 3-Bromo-N-methyl-benzamide (Intermediate 16) (110 Br [0120] A solution of 3-bromo-benzoyl chloride (2.93 g, 13.3 mmol, 1 eq) in 30mL THF
was stirred vigorously and treated with 2.0M methylamine in THF (15 mL, 29.4 mmol, 2.2 eq). A white precipitate was observed and the reaction was allowed to stir for 20 minutes.
Reaction was then poured onto ethyl acetate (100 mL) and washed with water (2 x 150 mL) and brine (1 x 150 mL). Organic phase cut from aqueous phase and dried over sodium sulfate, filtered and evaporated to afford the title intermediate 16 as a white powder. (2.29g, 82% yield).
EXAMPLE 30. 3-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-N-methyl-benzamide (Intermediate 17) NH
ON
CI
[0121] In a dry 50 mL round bottom flask, 2-chloro-5-methyl-pyrimidin-4-ylamine (0.3 g, 2.09 mmol, 1 equiv), 3-bromo-N-methyl-benzamide (0.489g, 2.29 mmol, 1.1 equiv), cesium carbonate (2.04g, 6.27 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene , (0.242 g, 0.418 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.191 g, 0.209 mmol, 0.1 equiv) were combined. Reactants were diluted with dioxane (20 mL), flushed with argon and outfitted with reflux condenser. Reaction was heated to reflux for 16 hours.
Reaction was then transferred into centrifuge tube, spun down, decanted and evaporated.
Resulting yellow solids were diluted with DCM and adsorbed onto silica gel.
Chromatography (gradient of 50% ethyl acetate in hexanes up to 100% ethyl acetate) afforded the title intermediate 17 as a pale yellow powder (0.25 g, 43%
yield). MS (ESI+):
277.01 (M+H), r.t. 1.92 mm.
EXAMPLE 31. N-Methyl-3-15-methyl-2-14-(2-pyrrolidin-1-yl-ethoxy)-phenylaminol-pyrimidin-4-ylaminol-benzamide TFA salt (Compound XVI) NH
N
XVI
[0122] The above-described intermediate 17 (0.068 g, 0.246 mmol, 1 eq), 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (0.061 g, 0.296 mmol, 1.2 eq), cesium carbonate (0.241 g, 0.74 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.029 g, 0.05 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.023 g, 0.025 mmol, 0.1 equiv) were combined in 15m1microwave vessel. Reactants were then diluted with 7 ml dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification afforded the TFA salt of the title product XVI
(0.084 g, 76%). MS (ESI+): 447.20 (M+H), r.t. = 1.53 min. 1H NMR (DMSO-d6): 8 1.87-1.91 (m, 2H), 2.02-2.06 (m, 2H), 2.16 (s, 3H), 2.79 (d, J=4.6 Hz, 3H), 3.11-3.15 (m, 2H), 3.57-3.61 (m, 5H), 4.23 (t, J=5.0 Hz, 3H), 6.84 (d, J=8.8 Hz, 2H), 7.34(d, J=8.9 Hz, 2H), 7.47 (t, J=7.9 Hz, 1H), 7.68-7.70 (m, 2H), 7.93 (s, 1H), 8.00 (s, 1H), 8.46-8.47 (m, 1H), 9.80 (bs, 1H), 9.93 (bs, 1H) 10.41 (bs, 1H).
EXAMPLE 32. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-14-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine TFA salt (Compound XVII) Cl gib 0 giF NH
"N
N
XVII
[0123] The above-described intermediate 7 (0.083 g, 0.293 mmol, 1 eq), 4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (0.073 g, 0.352 mmol, 1.2 eq), cesium carbonate (0.287 g, 0.879 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.034 g, 0.059 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.027 g, 0.029 mmol, 0.1 equiv) were combined in 15ml microwave vessel. Reactants were then diluted with 7 ml dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification afforded the TFA salt of the title product XVII (0.1 g, 75%). MS (ESP-): 454.13 (M+H), r.t. 1.82 min. 1H NMR (DMSO-do): 5 1.87-1.90 (m, 2H), 2.02-2.05 (m, 2H), 2.15 (s, 3H), 3.11-3.14(m, 2H), 3.58-3.61 (m, 5H), 3.70 (s, 3H), 4.26 (t, J-5.0 Hz, 3H), 6.91 (d, J=8.9 Hz, 2H), 7.23 (m, 1H), 7.34-7.4 (m, 4H), 7.93 (s, 1H), 9.63 (bs, 1H), 9.96 (bs, 1H) 10.40 (bs, 1H).
EXAMPLE 33. N-(2-Chloro-5-methyl-pyrimidin-4-y1)-N',N'-dimethvl-benzene-1,3-diamine (Intermediate 18) NH
=L N
LNCI
[0124] 2-Chloro-5-methyl-pyrimidin-4-ylamine (0.343 g, 2.38 mmol, 1 equiv), (3-bromo-pheny1)-dimethyl-amine (0.524g, 2.62 mmol, 1.1 equiv), cesium carbonate (2.3 g, 7.15 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.276 g, 0.476 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.218 g, 0.238 mmol, 0.1 equiv) were combined in 30m1 microwave vessel. Reactants were then diluted with 12m1 dioxane and microwaved for 25 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. Resulting solids were diluted with DCM and adsorbed onto silica gel.
Chromatography (gradient of 0% methanol in DCM up to 25% methanol in DCM) afforded the title intermediate 18 as orange solid (0.184 g, 29% yield). MS (ESI+):
263.02 (M+H), r.t.
=-- 1.72 mm.
EXAMPLE 34. /V4-(3-Dimethylamino-phenyl)-5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine TFA salt (Compound XVIII) NH
I
N 401 C)10 XVIII
[0125] The above-described intermediate 18 (0.092 g, 0.35 mmol, 1 eq), 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.087 g, 0.42 mmol, 1.2 eq), cesium carbonate (0.343 g, 1.05 mmol, 3 equiv), 4,5-bis(diphenyl phosphino)-9,9-dimethyl xanthene (0.041 g, 0.0702 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.032 g, 0.035 mmol, 0.1 equiv) were combined in a 15 ml microwave vessel. Reactants were then diluted with 7m1 dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification provided the TFA salt of the title compound XVIII
(0.035 g, 23%). MS (ESI+): 433.21 (M+H), r.t. = 1.52 min. 1H NMR (DMSO-d6): 6 1.87-1.90 (m, 2H), 2.03-2.06 (m, 2H), 2.15 (s, 3H), 2.87 (s, 6H), 3.12-3.15 (m, 2H), 3.57-3.60 (m, 4H), 3.70 (s, 3H), 4.25 (t, J=5.0 Hz, 3H), 6.34 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 6.82-6.90 (m, 4H), 7.20 (t, J=8.0 Hz, 1H), 7.39 (d, J=9.1 Hz, 2H), 7.85 (s, 1H), 9.63 (bs, 1H), 9.90 (bs, 1H) 10.39 (bs, 1H).
EXAMPLE 35. (2-Chloro-5-methyl-pyrimidin-4-y1)-(3,4-diehloro-phenyl)-amine (Intermediate 19) CI ei CI NH
N
I
CI
[0126] 2-chloro-5-methyl-pyrimidin-4-ylamine (0.408 g, 2.83 mmol, 1 equiv), 4-Bromo-1,2-dichloro-benzene (0.704 g, 3.12 minol, 1.1 equiv), cesium carbonate (2.8 g, 8.49 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.328 g, 0.57 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.26 g, 0.283 mmol, 0.1 equiv) were combined in 30m1 microwave vessel. Reactants were then diluted with 12ml dioxane and microwaved for 25 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. Resulting solids were diluted with DCM and adsorbed onto silica gel.
Chromatography (gradient of 15% ethyl acetate in hexanes up to 80% ethyl acetate in hexanes) afforded the title intermediate 19 as a pale yellow powder (0.366 g, 45% yield). MS
(ESI+): 287.97 (M+H), r.t. = 3.12 min.
EXAMPLE 36. N4-(3õ4-Dichloro-phenyl)-5-methyl-N244-(2-pyrrolidin4-171-ethor4)-phenyll-pyrimidine-2,4-diamine TFA salt (Compound XIX) CI
CI N H
N
N N
XIX
[0127] The above-described intermediate 19 (0.09 g, 0.313 mmol, 1 eq), 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.078 g, 0.376 mmol, 1.2 eq), cesium carbonate (0.307 g, 0.941 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.036 g, 0.063 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.029 g, 0.0314 mmol, 0.1 equiv) were combined in 15m1 microwave vessel. Reactants were then diluted with 7m1 dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification provided the TFA salt of the title compound XIX (0.056 g, 39%). MS (ESI+): 458.1 (M+H), r.t. = 1.93 min. 111 NMR (DMSO-d6): 5 1.87-1.91 (m, 2H), 2.03-2.06 (m, 2H), 2.14 (s, 3H), 3.12-3.15 (m, 3H), 3.57-3.60 (m, 4H), 4.26 (t, J=5.0 Hz, 2H), 6.97 (d, J=9.0 Hz, 1H), 7.40 (d, J=9 Hz, 2H), 7.60 (s, 2H), 7.97 (d, J=15.35 Hz, 2H), 9.46 (bs, 1H), 9.89 (bs, 1H) 10.17 (bs, 1H).
EXAMPLE 37. 4-{3-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylaminol-benzyll-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 20) CI is N
N N
[0128] (4-Chloro-3-methoxy-pheny1)-(2-chloro-5-methyl-pyrimidin-4-y1)-amine (0.092 g, 0.325 mmol, 1 eq), 4-(3-amino-benzyp-piperazine-1-carboxylic acid tert-butyl ester (0.114 g, 0.39 mmol, 1.2 eq), cesium carbonate (0.318 g, 0.975 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.038 g, 0.065 mmol, 0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.03 g, 0.0325 mmol, 0.1 equiv) were combined in a
15 ml microwave vessel. Reactants were then diluted with 7m1 dioxane and microwaved for 15 minutes at 160 C. Reaction vessel was then spun down, decanted and evaporated to dryness. HPLC purification afforded the TFA salt of the title intelinediate 20 (0.075 g, 43%).
MS (ESI+): 539.32 (M+H), r.t. = 2.09 mm.
EXAMPLE 38. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(3-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine TFA salt (Compound VC) CI el (NH
NLN N) XX
[0129] A stirring solution of the above-described intermediate 20 (0.075 g, 0.14 mmol, 1 eq) in DCM (6m1) was treated with TFA (2m1). After 2h, reaction solvents were evaporated and resulting residue triturated with ether to afford the title compound XX as white, hygroscopic solids, TFA salt. (0.05 g, 82%). MS (ESI+): 439.13 (M+H), r.t. =
1.67 mm. 1H
NMR (DMSO-d6): 5 2.17 (s, 3H), 2.89 (bs, 4H), 3.2 (bs, 4H), 3.68 (s, 3H), 3.82 (bs, 3H), 7.16-7.20 (m, 2H), 7.28 (t, J=7.7 Hz, 1H), 7.33 (d, J=2.3Hz, 1H), 7.39 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.49-7.51 (m, 1H), 7.98 (s, 1H), 8.87 (bs, 1H), 9.79 (bs, 1H) 10.57 (bs, 1H).
EXAMPLE 39. 2-(4-(2-(Pyrrolidin-1-yl)ethoxv)nhenylamino)-4-aminopyrimidine-5-earbonitrile (Intermediate 21) Ni H2 NC) .N o [01301 To a solution of 2,4-diaminopyrimidine-5-carbonitrile (135 mg, 1.00 mmol) in 1,4-dioxane (20 mL) was added 1-(2-(4-bromophenoxy)ethyl)pyrrolidine (270 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 174 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL
and hexane (50 mL) was added, the solid was collected by filtration. The crude product was purified by HPLC and afforded the title intenilediate 21 (32 mg, 10%).
EXAMPLE 40. 4-(2.,4-Diehloro-5-methoxypherrylamino)-2-(4-(2-(pyrrolidin-1-ybethoxy)phenvi-amino)pyrimidine-5-earbonitrile (Compound XXI) CI Abi CI
NC-L
I
N
NNS
XXI
[0131] To a solution of the above-described intermediate 21 (32 mg, 0.1 mmol) in 1,4-dioxane (10 mL) was added 1-bromo-2,4-diehloro-5-methoxybenzene (28 mg, 0.11 mmol), Cs2CO3 (97 mg, 0.3mmol), Pd2(dba)3 (7 mg, 0.0074 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 13 mg, 0.022 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was fjltered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by chromatograph (Si02/ CH2C12, then CH2C12 :
Me0H
NH3.1120 = 100: 10: 1) and afforded the title compound XXI (35 mg, 67%). 1H
NMk (500 MHz, DMSO-d6): 1.88-1.90 (m, 2H); 2.00-2.03 (in, 2H); 3.07-3.11 (m, 2H); 3.54-3.56 (m, 4H); 3.81 (s, 3H); 4.25 (br, 2H); 6.68 (br, 2H); 7.32 (br, 2H); 7.33 (s, 1H);
7.75 (s, 1H); 8.50 (s, 1H); 9.73 (br, 1H); 9.94 (br, 1H); 10.60 (br, 1H). MS (El): 499Ø
EXAMPLE 41. 2-(342-(Pyrro1idin-1-y1)ethoxy)pheny1amino)-4-aminopyrimidine-5-carbonitrile (Intermediate 22) NC N
I
N N
[01321 To a solution of 2,4-diaminopyrimidine-5-carbonitrile (145 mg, 1.07 mmol) in 1,4-dioxane (20 mL) was added 1-(2-(3-bromophenoxy)ethyl)pyrrolidine (290 mg, 1.07 mmol), Cs2CO3 (1.43 g, 4.4 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 174 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL
and hexane (50 mL) was added, the solid was collected by filtration. The crude product was purified by HPLC and afforded the title intelinediate 22 (55 mg, 16%).
EXAMPLE 42. 4-(2,4-Dichloro-5-methoxyphenylamino)-2-(3-(2-(pyrrolidin-1-ybethoxy)phenyikamino)pyrimidine-5-carbonitrile (Compound XXII) CI CI
I NCõ),-;
N
NN
XXII
[0133] To a solution of the above-described intermediate 22 (50 mg, 0.15 mmol) in 1,4-- dioxane (10 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (44 mg, 0.17 mmol), Cs2CO3 (200 mg, 0.62 mmol), Pd2(dba)3 (14 mg, 0.015 nunol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 27 mg, 0.05 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na2SO4).
The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXII (6 mg, 8%). 1HNMR (500 MHz, DMSO-d6): 1.87-1.89 (m, 2H); 1.90-2.03 (m, 2H); 3.04-3.08 (m, 2H); 3.52-3.56 (m, 4H); 3.80 (s, 3H); 4.23 (br, 2H);
6.62 (d, J = 6.4 Hz, 2H); 6.97 (br, 1H); 7.14 (br, 2H); 7.34 (s, 1H); 7.74 (s, 1H); 8.54 (s, 1H); 9.70 (br, 1H);
9.95 (br, 1H); 10.83 (br, 1H). MS (El): 499Ø
EXAMPLE 43. 2-Chloro-N-(2,4-dichloro-5-methoxvphenyI)-5-methylpyrimidin-4-amine (Intermediate 23) CI lei CI
Me NH
I
N C
[01341 To a solution of 2-chloro-5-methylpyrimidin-4-amine (44.8 mg, 0.31 mmol) in 1,4-dioxane (20 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (96 mg, 0.37 mmol), Cs2CO3 (408 mg, 1.25 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 70 mg, 0.12 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was used for next reaction without purification.
EXAMPLE 44. N2-(3-(2-(pyrrolidin-l-yflethoxy)pheny1)44-(2,4-diehloro-5-methoxypheny1)-5-methylpyrimidine-2,4-diamine (Compound XXIII) CI Cl Me() NH
N
-IN
N o"
XXIII
[0135] To a solution of the above-described intermediate 23 in 1,4-dioxane (10 mL) was added 3-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (77.3 mg, 0.38 mmol), Cs2CO3 (488 mg, 1.25 mmol), Pd2(dba)3 (28 mg, 0.03 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 53 mg, 0.09 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXIII (25 mg, 15%).
NMR (500 MHz, DMSO-d6): 1.87-1.89 (m, 2H); 1.90-2.03 (m, 2H); 2.18 (s, 3H);
3.04-3.08 (m, 2H); 3.52-3.56 (m, 4H); 3.80 (s, 3H); 4.24 (t, J = 5.0 Hz, 2H); 6.71 (d, J = 7.65 Hz, 1H); 6.91 (s, 1H); 6.96 (d, J = 8.5 Hz, 1H); 7.02 (t, J =8.2 Hz, 1H); 7.37 (s, 1H); 7.83 (s, 1H); .
8.02 (s, 1H); 10.09 (br, 1H); 10.66 (br, 1H); 10.82 (br, 1H). MS (El): 488.2.
EXAMPLE 45. 2-Chloro-N-(3-methoxyphenyI)-5-methylpyrimidin-4-amine (Intermediate 24) Me0 NH
CI
[0136] To a solution of 2-chloro-5-methylpyrimidin-4-amine (320 mg, 2.23 mmol) in 1,4-dioxane (40 mL) was added 1-bromo-3-methoxybenzene (458.5 mg, 2.45 mmol), Cs2CO3 (2.9 g, 8.9 mmol), Pd2(dba)3 (201 mg, 0.22 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 382 mg, 0.66 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine=(1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 24 (500 mg, 90%), was used for next reaction without further purification.
EXAMPLE 46. N2-(4-(2-(pyrrolidin-1-yl)ethoxy)pheny1)-/V4-(3-methoxypheny1)-5-methyl-pyrimidine-2,4-diamine (Compound XXIVA
Me NH
N N
XXIV
[0137] To a solution of the above-described intermediate 24 (240 mg, 0.96 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyn-olidin-l-yl)ethoxy)benzenamine (200 mg, 0.96 mmol), Cs2CO3 (1.3 mg, 4.0 mmol), Pd2(dba)3 (82 mg, 0.09 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 156 mg, 0.27 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by HPLC and afforded the title compound XXIV
(85 mg, 20%). 1H NMR (500 MHz, DMSO-d6): 1.89-1.91 (m, 2H); 1.98-2.05 (m, 2H); 2.16 (s, 3H);
3.07-3.12 (m, 2H); 3.52-3.56 (in, 4H); 3.73 (s, 3H); 4.33 (t, J = 4.5 Hz, 2H);
6.83-6.85 (m, 1H); 6.91 (d, J = 8.8 Hz, 2H); 7.17 (s, 1H); 7.34 (d, J = 8.8 Hz, 2H); 7.41 (t, J = 7.7 Hz, 1H);
7.56 (d, J = 7.7 Hz, 1H); 7.89 (s, 1H); 9.75 (s, 1H); 10.51 (s, 1H); 10.96 (br, 1H). MS (El):
420.2.
EXAMPLE 47. 3-(2-(4-(2-(Pyrrolidin-1-yflethoxy)phenylamino)-5-methylpyrimidin-ylamino)-phenol (Compound XXV) HO el NH
N C)1µ10 I
rµr N
XXV
[0138] To a solution of the above-described compound XXIV (50 mg, 0.1 mmol) in anhydrous CH2C12 (10 mL) was added 1.0 M BBr3 in CH2C12 (0.3 mL, 0.3 mmol).
The mixture was stirred for 3 h at room temperature. The saturated NaHCO3 (20 mL) was added and organic layer was separated. The aqueous was extracted with CH2C12 (3 x 10 mL).
Combined organic solution was dried (Na2SO4). The product was purified by HPLC
and afforded the title compound XXV (17 mg, 35%) as yellow solid. 1HNMR (500 MHz, DMSO-d6): 1.89 (br, 2H); 2.00 (br, 2H); 2.14 (s, 3H); 3.09 (br, 2H); 3.42 (br, 4H); 4.33 (br, 2H); 6.72 (d, J = 7.1 Hz, 1H); 6.91 (d, J = 8.4 Hz, 2H); 6.96 (d, J = 7.6 Hz, 1H); 7.00 (s, 1H);
7.18 (t, J = 8.0 Hz, 1H); 7.38 (d, J = 8.6 Hz, 2H); 7.88 (s, 1H); 9.70 (s, 1H); 9.74 (s, 1H);
10.55 (s, 1H); 11.09 (br, 1H). MS (El): 406.2.
EXAMPLE 48. 2-Chloro-5-methyl-N-(3-nitrophenyl)pyrimidin-4-amine (Intermediate 25_1 h e N
NCI
[0139] To a solution of 2-chloro-5-methylpyrimidin-4-amine (232 mg, 1.61 mmol) in 1,4-dioxane (40 mL) was added 1-bromo-3-nitrobenzene (359 mg, 1.78 mmol), Cs2CO3 (2.1 g, 6.4 mmol), Pd2(dba)3 (146 mg, 0.16 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 278 mg, 0.48 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The Organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 25, was used for next reaction without further purification.
EXAMPLE 49. N2-(442-(pyrrolidin-1-ybethoxy)pheny1)-5-methyl-/V4-(3-nitrophenybpyrimidine-2,4-diamine (Compound XXVI) N
XXVI
[0140] To a solution of the above-described intermediate 25 in 1,4-dioxane (40 mL) was added 4-(2-(pyrrolidin-l-yl)ethoxy)benzenamine (367 mg, 1.78 mmol), Cs2CO3 (2.1 g, 6.4 mmol), Pd2(dba)3 (146 mg, 0.16 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 218 mg, 0.48 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXVI (51 mg, 7%).
1H NMR (500 MHz, DMSO-d6): 1.89-1.92 (m, 2H); 1.98-2.05 (m, 2H); 2.21 (s, 3H);
3.10-3.12 (m, 2H); 3.52-3.57 (m, 4H); 4.33 (t, J = 4.8 Hz, 2H); 6.90 (d, J = 8.9 Hz, 2H); 7.32 (d, J
= 8.9 Hz, 2H); 7.67 (t, J = 8.2 Hz, 1H); 7.99 (s, 1H); 7.56 (dd, J = 8.4 Hz, J
= 1.8 Hz, 1H);
8.09 (d, J = 7.4 Hz, 1H); 8.45 (s, 1H); 10.14 (s, 1H); 10.60 (s, 1H); 11.17 (br, 1H). MS (El):
435.2.
EXAMPLE 50. 4-(2-Chloro-5-methylpyrimidin-4-ylamino)-2-ehlorobenzonitrile (Intermediate 26) CI NH
I
CI
[01411 To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-2-chlorobenzonitrile (217 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 26, was used for next reaction without further purification.
EXAMPLE 51. 4-(2-(442-(pyrrolidin-1-yflethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)-2-ehlorobenzonitrile (Compound XXVII) NC
CI NH
0,No , N N
XXVII
[01421 To a solution of the above-described intermediate 26 (140 mg, 0.5 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (113 mg, 0.55 mmol), Cs2CO3 (660 mg, 2.0 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 87 mg, 0.15 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by HPLC and afforded the title compound XXVII
(11.5 mg, 5%) as a yellow solid. IHNMR (500 MHz, DMSO-d6): 1.89-1.92 (m, 2H);- 1.98-2.05 (m, 2H); 2.20 (s, 3H); 3.08-3.13 (m, 2H); 3.56-3.59 (m, 4H); 4.36 (t, J = 4.9 Hz, 2H); 7.03 (d, J =
9.0 Hz, 2H); 7.40 (d, J = 9.0 Hz, 2H); 7.87 (br, 1H); 7.92 (d, J = 8.6 Hz, 1H); 8.03 (s, 1H);
8.16 (s, 1H); 9.82 (br, 1H); 10.37 (br, 1H); 10.90 (br, 1H). MS (El): 449.1.
EXAMPLE 52. N2-(442-(pyrrolidin-l-yOethoxy)pheny1)-5-methyl-/V4-p-tolylpyrimidine-2,4-diamine (Compound XXVIII1 NH
N
I
N
XXVIII
[0143] To a solution of the above-described intermediate 11 (50 mg, 0.16 nunol) in 1,4-dioxane (20 mL) was added 1-bromo-4-methylbenzene (28 mg, 0.16 mmol), Cs2CO3 (210 mg, 0.64 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 18 mg, 0.03 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXVIII (15.7 mg, 6%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.85-1.89 (m, 2H); 1.96-2.01 (m, 2H);
2.12 (s, 3H); 2.31 (s, 3H); 3.04-3.08 (m, 2H); 3.51-3.55 (m, 4H); 4.32 (br, 2H); 6.89 (br, 2H); 7.18 (br, 2H); 7.31 (br, 2H); 7.41 (br, 2H); 7.84 (s, 1H); 9.71 (s, 1H); 10.46 (s, 1H); 11.13 (br, 1H). MS (El): 404.2.
=
EXAMPLE 53. N2-(4-(2-(pyrrolidin-l-ybethoxy)pheny1)-N4-(4-chloro-3-methylpheny1)-5-methylpyrimidine-2,4-diamine (Compound XXIX) cl NH
XXIX
[0144] To a solution of the above-described intermediate 11 (80 mg, 0.25 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-l-chloro-2-methylbenzene (63 mg, 0.30 mmol), Cs2CO3 (326 mg, 1.0 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 36 mg, 0.06 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXIX (17.5 mg, 15%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.85-1.89 (m, 2H); 1.96-2.01 (m, 2H);
2.12 (s, 3H); 2.25 (s, 3H); 3.04-3.08 (m, 2H); 3.51-3.55 (m, 4H); 4.32 (br, 2H); 6.91 (br, 2H); 7.04 (br, 1H); 7.31 (br, 1H); 7.41 (br, 2H); 7.58 (s, 1H); 7.89 (br, 1H); 9.75 (s, 1H); 10.54 (s, 1H);
11.13 (br, 1H). MS (El): 438.1.
EXAMPLE 54. N-(4-(2-(pyrrolidin-1-ybethoxylpheny1)-4-benzy1-5-methylpyrimidin-amine (Compound ,00() N CriLD
N N
XXX
[0145] To a solution of 4-benzy1-2-chloropyrirnidine (286 mg, 1.4 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (288 mg, 1.4 mmol), Cs2CO3 (1.82 g, 5.6 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound VCX (42 mg, 10%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.89 (br, 2H); 2.00 (br, 2H); 3.09 (br, 2H);
3.54 (br, 4H); 4.31 (br, 2H); 6.71 (d, J = 5.0 Hz, 1H); 6.93 (d, J = 8.8 Hz, 2H); 7.24 (m, 1H);
7.32 (m, 4H); 7.62 (d, J = 8.8 Hz, 2H); 8.32 (d, J = 5.0 Hz, 1H); 9.66 (s, 1H); 10.92 (br, 1H).
MS (E1): 375.2.
EXAMPLE 55. 44(1H-indo1-4-yl)methyl)-N-(4-(2-(pyrrolidin-1-yllethoxy)pheny1)-5-methylpyrimidin-2-amine (Compound XXXI) HN
NH
N
N
VOCI
[0146] To a solution of the above-described intermediate 11 (460 mg, 1.46 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-1H-indole (288 mg, 1.46 mmol), Cs2CO3 (1.95 g, 6.0 mmol), Pd2(dba)3 (128 mg, 0.14 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 243 mg, 0.42 mmol). The mixture was heated under reflux for overnight under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound 300(1 (66 mg, 10%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.87 (br, 2H); 1.98-2.05 (m, 2H);
2.21 (s, 3H); 3.15 (br, 2H); 3.52 (br, 2H); 3.69 (br, 2H); 4.24 (br, 2H); 6.33 (s, 1H);
6.60 (br, 2H);
6.82 (br, 1H); 6.92 (br, 1H); 7.02 (br, 2H); 7.16 (br, 1H); 7.26 (br, 1H);
7.43 (m, 1H); 7.88 (m, 1H); 10.11 (s, 1H); 11.40 (s, 1H). MS (E1): 429.1.
EXAMPLE 56. 2-Chloro-5-metiryl-N-(naphthalen-1-y1)pyrimidin-4-amine (Intermediate 27) MTV
NH
N
[0147] To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 mL) was added 1-bromonaphthalene (227 mg, 1.1 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na9SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title interrnediate 27, was used for next reaction without further purification.
EXAMPLE 57. N-(4-(2-(pyrrolidin-l-ybethoxv)pheny1)-5-methyl-4-(naphthalen-1-y1)pyrimidin-2-amine (Compound XXXII) NH
N
I
N
XXXII
[0148] To a solution of the above-described inteimediate 27 (235 mg, 0.87 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (183 mg, 0.87 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 87 mg, 0.15 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by HPLC and afforded the title compound VOUI
(89 mg, 21%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.88-1.90 (m, 2H); 1.97-2.03 (m, 2H); 2.30 (s, 3H); 3.03-3.08 (m, 2H); 3.50-3.53 (m, 4H); 4.21 (t, J = 4.9 Hz, 2H); 6.50 (d, J =
7.2 Hz, 2H); 6.82 (d, J = 8.6 Hz, 2H); 7.54 (d, J = 7.8 Hz, 2H); 7.57-7.61 (m, 1H); 7.63 (t, J =
7.4 Hz, 1H); 7.89 (d, 3 = 8.3 Hz, 2H); 7.95 (s, 1H); 8.02 (d, 3 = 8.3 Hz, 1H);
8.08 (d, J = 7.7 Hz, 1H); 10.37 (s, 1H); 10.43 (s, 1H); 10.93 (br, 1H). MS (El): 440.1.
EXAMPLE 58. 1-(2-Chloro-5-methylpyrimidin-4-yflisoquinoline (Intermediate 28) I.
N NH
NCI
[0149] To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 mL) was added 1-chloroisoquinoline (164 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and.4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 28, was used for next reaction without further purification.
EXAMPLE 59. N-(4-(2-(pyrrolidin-l-yl)ethoxy)nheny1)-4-(isocininolin-1-y1)-5-methylpyrimidin-2-amine (Compound Valli) NH
I
N N
Wail [01501 To a solution of the above-described intermediate 28 (90 mg, 0.33 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-ypethoxy)benzenamine (76 mg, 0.37 mmol), Cs2CO3 (391 mg, 1.2 mmol), Pd2(dba)3 (28 mg, 0.03 mmol), and 4,5-bis(diphenylphosphino)-9,9-ditnethyxanthene (Xant Phos, 52 mg, 0.09 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by HPLC and afforded the title compound XXXIII
(21 mg, 15%) as a yellow solid. 111NMR (500 MHz, DMSO-d6): 1.64-1.70 (m, 6H); 2.23 (s, 3H);
2.78 (t, J = 5.9 Hz, 2H); 4.04 (t, J = 5.9 Hz, 2H); 6.38 (d, J = 7.2 Hz, 1H);
6.93 (d, J = 9.0 Hz, 2H); 6.97 (d, J = 7.2 Hz, 1H); 7.45 (br, 1H); 7.57 (d, J = 8.8 Hz, 1H); 7.58-7.62 (m, 1H);
7.70-7.78 (m, 2H); 8.04 (s, 1H); 8.75 (d, J = 8.1 Hz, 1H); 9.06 (s, 1H); 9.19 (s, 1H). MS (El):
441.2.
EXAMPLE 60. N2-(4-(2-(pyrrolidin-1-iflethoxy)pheny1)-/V4-(3-.
(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine (Compound XXXIV) 3," NH
N N
)(XXIV
[0151] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (143 mg, 1.0 mmol), 1-bromo-3-(trif1uoromethyl)benzene (225 mg, 1.0 mmol), Pd2(dba)3 (9.0 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) were suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 15 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in yam . The residue on purification using HPLC gave /V4-(3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine as an off white solid (192 mg, 67%). MS (ESI+): m/z 288 (M+H)+. A mixture of /V4-(3-(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine (28.7 mg, 0.1 mmol) and 4-(2-(pyrrolidin-1-ypethoxy)benzenamine (22 mg, 0.12 mmol) were dissolved in acetic acid (5 mL) and heated under microwave at 150 C for 10 min. The mixture was cooled to room temperature and acetic acid removed under reduced pressure. The residue was purified by HPLC
to afford the title compound LIOCIV as brown solid (16 mg, 35%). 1H NMR (500 MHz, DMSO-d6):
1.65-1.71 (m, 4H), 2.11 (s, 3H), 2.45-2.55 (m, 4H), 2.74 (t, J= 6.0 Hz, 2H), 3.98 (t, J= 6.0 Hz, 2H), 6.76 (d, J= 9.0 Hz, 2H), 7.35 (d, J= 5.1Hz, 1H), 7.45-7.57 (m, 3H), 7.9-7.97 (m, 2H), 8.20 (d, J= 7.6 Hz, 1H), 8.41(s, 1H), 8.85 (s, 1H), nilz 458 (M+H) .
EXAMPLE 61. 2-ehloro-N-(4-(trifluoromethyl)pheny1)-5-methylpyrimidin-4-amine (Intermediate 29) NH
[0152] A suspension of 2-chloro-5-methylpyrimidin-4-amine (159 4, 1.2 mmol), bromo-4-(trifluoromethyl)benzene (150 mg, 1.0 mmol), potassium tert-butoxide (224 mg, 2.0 mmol), Xantphos (120 mg, 0.2 mmol), and palladium acetate (26 mg, 0.1 mmol) was sealed in a microwave reaction tube and irradiated at 160 C for 15 min. The mixture was allowed to cool to room temperature, the solids were filtered using DCM to rinse, and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane to Et0Ac) to afford the title intermediate 29 (128.7 mg, 43%) as a white solid. MS (ESI+): nilz 288 (M+H)+.
EXAMPLE 62. N2-(4-(2-(pyrrolidin-1-ybethoxy)pheny1)-N4-(4-(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine (Compound )00(V) NH
I. CI,No N
XXXV
[0153] A mixture of the above-described intermediates 29 (128 mg, 0.5 mmol) and 6 (212 mg, 1.0 mmol) were suspended in acetic acid (5 mL) and heated at 75 C for 18 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was basified with sat., aq NaHCO3 (50 mL) and extracted with DCM
(2x50 mL). The organic layer was concentrated in vacuo and the crude product purified by reverse phase flash chromatography on C18 (water to CH3CN, 0.1% TFA). The aqueous fractions were neutralized with sat, aq NaHCO3 and extracted with Et0Ac. The organics were concentrated in vacuo and the residue taken up in DCM. HC1 in dioxane was added along with ether and the resulting solid filtered to afford the hydrochloride salt of the title compound XXXV (166 mg, 70%) as a grey solid. Ili NMR (500 MHz, DMSO-d6): 1.80-1.95 (in, 2H), 1.95-2.10 (in, 2H), 2.19 (s, 3H), 3.05-3.20 (in, 2H), 3.55-3.65 (m, 6H), 4.33 (t, J= 4.7 Hz, 2H), 6.97 (d, J= 8.7 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.73 (d, J
= 8.5 Hz, 2H), 7.83 (d, = 8.0 Hz, 2H), 7.94 (s, 1H), 9.92 (hr s, 1H), 10.44 (hr s, 1H), 10.85 (hr s, 1H); MS
(ESI+): ni/z 458.5 (M+14)+.
EXAMPLE 63. Benzo[1,31dioxo1-4-y1-(2-ehloro-5-methyl-pyrimidin-4-171)-amine (Intermediate 30) NH
N
I
CI
[0154] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.4 g, 9.7 mmol), 4-bromo-benzo[1,3]dioxole (2.0 g, 10 rnrnol), Pd2(dba)3 (0.80 g, 0.87 mmol), Xantphos (1.0 g, 1.7 mmol) and cesium carbonate (6.3 g, 19 mmol) was suspended in dioxane (40 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to 50% Et0Ac/hexanes) to afford the title compound (1.0 g, 39%) as a white solid.
1HNMR (500 MHz, DMSO-d6): 6 2.13 (s, 3H), 5.99 (s, 2H), 6.80-6.90 (m, 3H), 8.01 (s, 1H), 8.92 (s, 1H). MS (ES+): m/z 264 (M+H)+.
EXAMPLE 64. /V4-Benzo[1,31dioxo1-4-y1-5-methyl-N2-1442-pyrro1idin-1-yl-ethoxy)-=
phenyll-pyrimidine-2,4-diamine (Compound XXXVI) Aki 0 NH
XXXVI
101551 A mixture of intermediate 30 (0.25 g, 0.95 mmo1) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.40 g, 1.9 mmol) in acetic acid (15 mL) was heated at 100 C for 20 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7 with 10%
NaOH solution. The resulting solution was extracted with Et0Ac (2 x 30 mL) and the organic layer separated. The organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 20% Me0H/DCM) to afford the title compound (0.14 g, 34%) as a white solid.
[0156] 1H NMR (500 MHz, DMSO-d6): 8 1.65-1.75 (m, 4H), 2.06 (s, 3H), 2.55-2.65 (m, 4H), 2.78-2.88 (m, 2H), 3.98 (t, J= 5.8 Hz, 2H), 5.89 (s, 2H), 6.65 (d, J= 9.0 Hz, 2H), 6.79-6.84 (m, 2H), 6.89 (dd, J=7.7, 1.7 Hz, 1H), 7.45 (d, J= 9.1 Hz, 2H), 7.81 (s, 1H), 8.23 (s, 1H), 8.73 (s, 1H). MS (ES+): m/z 434 (M+H)+.
EXAMPLE 65. /V4-Benzor1,31dioxol-4-y1-5-methyl-N2-[4-(4-methyl-piperazin-1-y1)-pheny11-pyrimidine-2,4-diamine (Compound )(XXVIII
0-\
So NH
N N) I
N
XXXVII
[0157] A mixture of intermediate 30 (0.10 g, 0.38 mmol) and 4-(4-methyl-piperazin-l-y1)-phenylamine (0.12 g, 0.51 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (DCM to 15% Me0H/DCM) to afford the title compound (22 mg, 14%) as a light red solid.
[0158] 11-1 NMR (500 MHz, DMSO-d6): 8 2.06 (s, 3H), 2.21 (s, 3H), 2.44 (t, J= 4.8 Hz, 4H), 2.97 (t, J= 4.9 Hz, 4H), 5.89 (s, 2H), 6.67 (d, J= 9.1 Hz, 2H), 6.80-6.86 (m, 2H), 6.91 (dd, J= 7.6, 1.7 Hz, 1H), 7.41 (d, J= 9.0 Hz, 2H), 7.79 (s, 1H), 8.17 (s, 1H), 8.63 (s, 1H).
MS (ES+): nz/z 419 (M+H)+.
EXAMPLE 66. (4-Chloro-3-methoxv-pheny1)-(2-chloro-5-methyl-avrimidin-4-y1)-amine (Intermediate 31) CI I.
NH
I
CI
[0159] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-bromo-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to 40% Et0Ac/hexanes) to afford the title compound (0.55 g, 55%) as a yellow solid.
[0160] 1H NMR (500 MHz, DMSO-d6): 8 2.18 (s, 3H), 3.85 (s, 3H), 7.35 (dd, J= 8.6, 2.3 Hz, 1H), 7.39 (d, J= 8.7 Hz, 1H), 7.56 (d, J= 2.3 Hz, 1H), 8.09 (d, J= 0.9 Hz, 1H), 8.91 (s, 1H). MS (ES+): in/z 284 (M+H)+.
EXAMPLE 67. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(4-pyrazol-1-ylmethyl-pheny1)-pyrimidine-2,4-diamine (Compound X.XXVIII) , CI dh Me0 NH
"N
1\r N
XXXVIII
[0161] A suspension of intennediate 31 (0.20 g, 0.70 mmol), 4-pyrazol-1-ylmethyl-phenylamine (0.14 g, 0.81 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), Xantphos (50 mg, 0.086 mmol) and cesium carbonate (0.50 g, 1.5 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC.
The fractions were combined and poured into saturated NaHCO3 solution (40 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.13 g, 44%).
1H NMR (500 MHz, DMSO-d6): 8 2.11 (s, 3H), 3.74 (s, 3H), 5.22 (s, 2H), 6.25 (t, J = 2.1 Hz, 1H), 7.08 (d, J= 8.6 Hz, 2H), 7.27 (d, J= 9.3 Hz, 1H), 7.40-7.45 (m, 3H), 7.60 (d, J¨ 8.6 Hz, 2H), 7.75 (d, J= 1.8 Hz, 1H), 7.91 (s, 1H), 8.36 (s, 1H), 9.04 (s, 1H) MS (ES+): in/z 421 (M+H)+.
EXAMPLE 68. 5-Methyl-N2-[4-(4-methyl-piperazin-1-y1)-phenyl]-pyrimidine-2,4-diamine (Intermediate 321 a N
[0162] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.0 g, 6.9 mmol) and 4-(4-methyl-piperazin-1-y1)-phenylamine (1.5 mL, 7.8 mmol) in acetic acid (15 mL) was heated at 100 C for 2.5 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. After filtration and washed with water, the title compound was obtained as a grey solid (1.3 g, 63%).
[0163] 1H NMR (500 MHz, DMSO-d6): 8 1.88 (s, 3H), 2.21 (s, 3H), 2.21 (s, 3H), 2.44 (t, J= 4.8 Hz, 4H), 3.00 (t, J= 4.8 Hz, 4H), 6.27 (s, 2H), 6.79 (d, J= 9.0 Hz, 2H), 7.57 (d, J=-9.0 Hz, 2H), 7.63 (s, 1H), 8.42 (s, 1H). MS (ES+): nilz 299 (M+H)+.
EXAMPLE 69. 1V444-Chloro-3-methoxy-pheny1)-5-methyl-N244-(4-methyl-piperazin-1-y1)-phenyli-pyrimidine-2õ4-diamMe (Compound X.,XXIX) CI..
Me0 NH
N
=N N
VOCIX
[0164] A suspension of interinediate 32 (0.30 g, 1.0 mmol), 4-bromo-l-chloro-2-methoxy-benzene (0.20 mL, 1.5 mmol), Pd2(dba)3 (50 mg, 0.055 mmol), Xantphos (65 mg, 0.11 mmol) and cesium carbonate (0.70 g, 2.1 mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC.
The fractions were combined and poured into saturated NaHCO3 solution (40 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic 105 t..
layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/5, 30 mL). After filtration, the title compound was obtained as an off white solid (0.20 g, 46%).
[0165] 1H NMR (500 MHz, DMSO-d6): 6 2.09 (s, 3H), 2.21 (s, 3H), 2.45 (t, J=
4.9 Hz, 4H), 3.02 (t, J= 4.9 Hz, 4H), 3.73 (s, 3H), 6.79 (d, J= 9.1 Hz, 2H), 7.27 (d, J= 8.6 Hz, 1H), 7.42-7.47 (m, 3H), 7.49 (d, J= 2.3 Hz, 1H), 7.86 (s, 1H), 8.28 (s, 1H), 8.72 (s, 1H). MS
(ES+): m/z 439 (M+H)+.
EXAMPLE 70. N444-Chloro-3-methoxy-pheny1)-5-methyl-N2-(4-morpholin-4-yl-phenyb-pyrimidine-2,4-diamine (Compound XL) a (61 Me0 IV NH
N) N N
XL
[0166] A mixture of intermediate 31(0.10 g, 0.35 mmol) and 4-morpholin-4-yl-phenylamine (80 mg, 0.45 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (DCM to 10%
Me0H/DCM) to afford the title compound (55 mg, 37%) as a light brown solid.
[0167] NMR (500 MHz, DMSO-d6): 82.10 (s, 3H), 3.00 (t, J= 4.8 Hz, 4H), 3.71-3.76 (m, 7H), 6.80 (d, J= 9.0 Hz, 2H), 7.28 (d, J= 8.6 Hz, 1H), 7.45 (dd, J= 8.7, 2.2 Hz, 1H), 7.47-7.50 (m, 3H), 7.87 (s, 1H), 8.29 (s, 1H), 8.75 (s, 1H). MS (ES+): m/z 426 (M+H)#.
EXAMPLE 71. M-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(4-pyrazol-1-yl-pheny1)-pyrimidine-2,4-diamine (Compound XLI) c, Me() NH
XLI
[0168] A mixture of intefinediate 31 (90 mg, 0.32 mmol) and 4-pyrazol-1-yl-phenylamine (70 mg, 0.44 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by HPLC. The corrected fractions were combined and concentrated to afford the title compound (40 mg of TFA salt, 24%) as a white solid.
[0169] 1H NMR (500 MHz, DMSO-d6): 5 2.17 (s, 3H), 3.75 (s, 3H), 6.54 (t, J=
1.9 Hz, 1H), 7.30 (d, J= 6.6 Hz, 1H), 7.39 (d, J.= 2.1 Hz, 1H), 7.40 (d, J= 8.6 Hz, 1H), 7.59 (d, 8.9 Hz, 2H), 7.71 (d, J= 8.9 Hz, 2H), 7.73 (d, J= 1.6 Hz, 1H), 7.93 (s, 1H), 8.41 (d, J= 2.5 Hz, 1H), 9.41 (s, 1H), 10.05 (s, 1H). MS (ES+): nilz 407 (M+H)+.
EXAMPLE 72. /0-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(4-piperidin-l-yl-pheny1)-pyrimidine-2,4-diamine [XLII) CI
Me0 NH
NN
XLII
[0170] A mixture of intermediate 31 (0.11 g, 0.39 mmol) and 4-piperidin-1-yl-phenylamine (90 mg, 0.51 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture neutralized with 10% NaOH solution until solid precipitated.
The solid was filtered and then purified by flash chromatography on silica gel (hexanes to 70%
Et0Ac/hexanes)to afford the title compound (10 mg, 6%) as a light brown solid.
[0171] 1HNMR (500 MHz, DMSO-d6): 8 1.48-1.53 (m, 2H), 1.59-1.65 (m, 4H), 2.09 (s, 3H), 3.00 (t, J= 5.4 Hz, 4H), 3.73 (s, 3H), 6.78 (d, J= 9.0 Hz, 2H), 7.27 (d, J= 8.7 Hz, 1H), 7.40-7.47 (m, 3H), 7.50 (d, J= 2.2 Hz, 1H), 7.86 (s, 1H), 8.28 (s, 1H), 8.71 (s, 1H). MS
(ES+): in/z 424 (M+H)+.
EXAMPLE 73. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl- N244-(4-methyl-piperazin-1-ylmethyl)-phenyll-pyrimidine-2,4-diamine (XLIII) =
CI
Me0 IqVI NH
\/11 7)1, NIIN
N N
XLIII
[0172] A suspension of intermediate 31 (50 mg, 0.18 mmol), 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (50 mg, 0.24 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol) and cesium carbonate (0.12 g, 0.37 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 10% Me0H/DCM)to afford the title compound (35 mg, 44%) as an off white solid.
[0173] IHNMR (500 MHz, DMSO-d6): 8 2.11 (s, 3H), 2.15 (s, 3H), 2.20-2.45 (m, 8H), 3.35 (s, 2H), 3.75 (s, 3H), 7.07 (d, J= 8.5 Hz, 2H), 7.28 (d, J= 8.5 Hz, 1H), 7.44 (dd, J= 8.7, 2.3 Hz, 1H), 7.47 (d, J= 2.3 Hz, 1H), 7.57 (d, J= 8.5 Hz, 2H), 7.91 (s, 1H), 8.36 (s, 1H), 8.98 (s, 1H). MS (ES+): in/z 453 (M+H)+.
EXAMPLE 74. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl- N244-piperazin-1-yl-pheny1)-pyrimidine-2,4-diamine (Compound XLIV) CI
Me0 NH (NH
\)L N
N N
XLIV
[0174] A mixture of intermediate 31 (0.20 g, 0.70 mmol) and 4-(4-amino-pheny1)-piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 0.79 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C
for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (40 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.10 g, 33%).
[0175] 1HNMR (500 MHz, DMSO-d6): 62.10 (s, 3H), 3.16 (s, 8H), 3.73 (s, 3H), 6.83 (d, J= 9.0 Hz, 2H), 7.29 (d, J= 8.8 Hz, 1H), 7.44 (dd, J= 8.7, 2.1 Hz, 1H), 7.49-7.52 (m, 3H), 7.88 (s, 1H), 8.32 (s, 1H), 8.81 (s, 1H) MS (ES+): m/z 425 (M+H)+.
EXAMPLE 75. N-tert-Buty1-3-{5-methy1-2-[4-(4-methyl-piperazin-1-y1)-phenylamino]-pyrimidin-4-ylaminol-benzenesulfonamide (Compound XLV) H
N
NH
ON Nõ) tNN
XLV
[01761 A suspension of intermediate 32 (0.30.g, 1.0 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (0.35 g, 1.2 mmol), Pd2(dba)3 (60 mg, 0.066 mmol), Xantphos (70 mg, 0.12 mmol) and cesium carbonate (0.70 g, 2.1 mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (40 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/7, 40 mL). After filtration, the title compound was obtained as an off white solid (0.30 g, 59%).
[0177] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.11 (s, 3H), 2.22 (s, 3H), 2.45 (t, J= 4.7 Hz, 4H), 3.02 (t, J= 4.8 Hz, 4H), 6.81 (d, J= 9.1 Hz, 2H), 7.45-7.52 (m, 4H), 7.56 (s, 1H), 7.89 (s, 1H), 8.10-8.16 (m, 2H), 8.51 (s, 1H), 8.70 (s, 1H) MS (ES+):
in/z 510 (M+H)+.
EXAMPLE 76. N-tert-Buty1-3-(2-eh1oro-5-methy1-nvrimidin-4-y1amino)-benzenesulfonamide (Intermediate 33) Ho 411 N'g NH
N
I
CI
[0178] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium calbmlate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in Et0Ac and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was Used in the next step without purification. MS (ES+): m/z 355 (M+H)+.
EXAMPLE 77. N-tert-Butyl-345-methy1-2-(4-morpho1in-4-Amethyl-pheny1amino)-= pyrimidin-4-ylamino[-benzenesulfonamide (Compound XLVI1 NH
N N
NN LO
XLVI
[0179] A mixture of intermediate 33 (0.50 g, 1.4 mmol), 4-morpholin-4-ylmethyl-phenylamine (0.35 g, 1.8 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (1.0 g, 3.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (50 mL). The combined aqueous layers were extracted with Et0Ac (2 x 50 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.23 g, . 31%).
[0180] IFINMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.13 (s, 3H), 2.28-2.34 (m, 4H), 3.35 (s, 2H), 3.55 (t, .1= 4.8 Hz, 4H), 7.10 (d, J= 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.57 (s, 1H), 7.59 (d, J= 8.5 Hz, 2H), 7.94 (s, 1H), 8.10 (s, 1H), 8.13-8.16 (m, 1H), 8.58 (s, 1H), 8.95 (s, 1H). MS (ES+): /72/z 511 (M+H)+.
EXAMPLE 78. N-tert-Buty1-3-{5-methy1-2-[4-(4-oxy-morpholin-4-ylmethyl)-phenylamino[-pyrimidin-4-ylaminol-benzenesulfonamide (Compound XLVH) Or-NH
NH
N+Th kNN ,-0 XLVII
[0181] A solution of the above-described compound XLVI (30 mg, 0.06 mrnol) and chloroperbenzoic acid (77%, 14 mg, 0.06 mmol) in chloroform (30 mL) was strred at room temperature for 1 hour. The solvent was removed by rotovap and the resulting mixture was purified by silica gel with 20% CH3OH/CHC13 as an eluent to afford the title compound as an off-white solid (15 mg, 48%).
[0182] 1H
NMR (500 MHz, DMSO-d6): 8 1.12 (s, 911), 2.14 (s, 3H), 2.71 (d, J= 10.9 Hz, 214), 3.63 (d, J= 9.9 Hz, 2H), 4.08 (t, J= 11.6 Hz, 2H), 4.28 (s, 2H), 7.38 (d, J= 8.5 Hz, 2H), 7.50 (d, J 5.0 Hz, 2H), 7.61 (s, 111), 7.66 (d, J-= 8.5 Hz, 2H), 7.96 (s, 1H), 8.13 (m, 2H), 8.63 (s, 1H), 9.13 (s, 111). MS (ES+): in/z 527 (M+H)+.
EXAMPLE 79. N-tert-Buty1-345-methyl-244-pyrazol-1-14-phenylamino)-pyrimidin-4-vlaminol-benzenesulfonamide (Compound XLVIII) NH \
8 -õ), NN
XLVIII
[0183] A
mixture of intermediate 33 (0.10 g, 0.28 mrnol) and 4-pyrazol-1-yl-phenylamine (50 mg, 0.31 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken up in water (20 mL) and neutralized with 10% NaOH solution until solid precipitated. The brown solid was filtered and then purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).
[0184] 1HNMR
(500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.15 (s, 3H), 6.49 (t, J= 2.2 Hz, 1H), 7.50-7.55 (m, 2H), 7.58 (s, 1H), 7.62 (d, J= 9.1 Hz, 2H), 7.68 (d, J= 1.3 Hz, 1H), 7.77 (d, J= 9.1 Hz, 2H), 7.96 (s, 1H), 8.11 (s, 1H), 8.13-8.16 (m, 1H), 8.33 (d, J=
2.5 Hz, 1H), 8.64 (s, 1H), 9.17 (s, 1H). MS (ES+): m/z 478 (M+H)+.
EXAMPLE 80. N-tert-Buty1-345-methy1-2-(6-piperazin-1-yl-pyridin-3-ylamino)-pyrimidin-4-ylamino[-benzenesulfonamide (Compound XLDC) HO lel >1\l'g NH
I I
Nr XLIX
[0185] A
mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(5-amino-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.32 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C
for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was dissolved in DCM (5 mL) and 30% TFA/DCM (6 mL) added. The mixture was stirred at room temperature for lh, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2504 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (10 mg, 7%).
[0186] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.11 (s, 3H), 2.83 (t, J=
5.0 Hz, 4H), 3.28-3.33 (in, 4H), 6.73 (d, J= 9.1 Hz, 1H), 7.40-7.49 (in, 2H), 7.57 (s, 1H), 7.86 (dd, J
= 9.1, 2.7 Hz, 1H), 7.88 (s, 1H), 8.10-8.16 (in, 2H), 8.28 (d, J= 2.5 Hz, 1H), 8.53 (s, 1H), 8.72 (s, 1H). MS (ES+): nilz 497 (M+H)+.
EXAMPLE 81. N-tert-Buty1-3-[5-methyl-244-pyrazol-1-ylmethyl-phenylamino)-pyrimidin-4-ylamino1-benzenesulfonamide (Compund L) Ho N I I
NH
N 401 NI:: I \ji N N
[0187] A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-pyrazol-1-ylmethyl-phenylamine (50 mg, 0.29 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (12 mg, 9%).
[0188] 1HNMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.13 (s, 3H), 5.21 (s, 2H), 6.24 (t, J= 1.9 Hz, 1H), 7.08 (d, J= 8.5 Hz, 2H), 7.27-7.50 (m, 3H), 7.56 (s, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 2.1 Hz, 1H), 7.94 (s, 1H), 8.14 (d, J= 7.9 Hz, 1H), 8.59 (s, 1H), 9.01 (s, 1H). MS (ES+): nilz 492 (M+H)+.
EXAMPLE 82. 5-Methyl-N2-[3-(piperidine-1-su1fony1)-pheny11-pyrimidine-2,4-diamine (Intermediate 34) N
N
N N
it [0189] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mrnol) and 3-(piperidine- 1-sulfony1)-phenylamine (0.50 g, 2.1 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to ¨9 with 10% NaOH solution. The resulting solution was extracted with Et0Ac (2 x 30 mL) and the organic layer separated.
The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated in vacuo and the crude product (-0.6 g) used in the next step without purification. MS (ES+): m/z 348 (M+H)+.
EXAMPLE 83. N-tert-Buty1-3-{5-methy1-2-[3-(piperidine-1-sulfony1)-phenylaminol-pyrimidin-4-ylaminolt-benzenesulfonamide (Compound LI) HO si=¨N
NH
1.1.1 40 0 NN
LI
[01901 A suspension of intermediate 34 (0.10 g, 0.29 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (84 mg, 0.29 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (20 mg, 12%).
[0191] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 1.30-1.40 (m, 2H), 1.50-1.56 (m, 4H), 2.16 (s, 3H), 2.88 (t, J= 5.3 Hz, 4H), 7.17 (d, J= 7.8 Hz, 1H), 7.43 (t, J= 8.0 Hz, 1H), 7.59-7.60 (m, 2H), 7.58 (s, 1H), 8.13 (s, 1H), 7.16 (dd, J= 7.9, 1.9 Hz, 1H), 8.18-8.22 (m, 1H), 8.67 (s, 1H), 9.37 (s, 1H). MS (ES+): 171/Z 559 (M+H)+.
EXAMPLE 84. N-tert-Buty1-345-methy1-2-14-(4-methyl-piperazin4-ylmethvb-pheny1aminol-pyrimidin-4-y1aminol-benzenesulfonamide (Compound LII) HQ
NH
N N
1\17. N
LII
[0192] A suspension of intetinediate 33 (0.10 g, 0.28 mmol), 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (65 mg, 0.32 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (53 mg, 36%).
[0193] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.13 (s, 3H), 2.15 (s, 3H), 2.20-2.45 (m, 4H), 3.25-3.40 (m, 6H), 7.08 (d, J.= 8.6 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1H), 7.57 (d, J= 8.6 Hz, 2H), 7.94 (s, 1H), 8.09 (s, 1H), 8.13-8.16 (m, 1H), 8.58 (s, 1H), 8.94 (s, 1H). MS (ES+): m/z 524 (M+H)+.
EXAMPLE 85. N-tert-Buty1-3-15-methy1-2-(4-piperazin-1-y1-3-trifluoromethyl-pheny1amino)-pyrimidin-4-y1amino1-benzenesu1fonamide (Compound LIII) HO
N N
LIII
[0194] A
mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-amino-2-trifluoromethyl-pheny1)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.29 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was dissolved in DCM (5 mL) and 50% TFA/DCM (6 mL) added.
The mixture was stirred at room temperature for 2h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and. the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (42 mg, 26%).
[0195] 1H
NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.14 (s, 3H), 2.70-2.75 (m, 4H), 2.80-2.85 (m, 4H), 7.36 (d, J= 8.5 Hz, 2H), 7.45-7.52 (in, 2H), 7.55 (s, 1H), 7.90-8.00 (m, 3H), 8.07 (s, 1H), 8.15 (d, J= 7.6 Hz, 1H), 8.63 (s, 1H), 9.22 (s, 1H) MS
(ES+): m/z 564 (M+H)+.
EXAMPLE 86. 3-{2-14-(4-Acetyl-piperazin-1-0.)-3-trifluoromethyl-phenylamino]-5-methyl-pyrimidin-4-ylaminol-N-tert-butyl-benzenesulfonamide (Compound LIV) H 0 el N
LIV
[0196] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 144-(4-amino-2-trifluoromethyl-pheny1)-piperazin- l-y1]-ethanone (0.1 g, 0.35 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (64 mg, 38%).
[0197] NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.04 (3, H), 2.14 (s, 3H), 2.73 (t, J
= 4.9 Hz, 2H), 2.79 (t, J= 4.7 Hz, 2H), 3.50-3.60 (in, 4H), 7.40 (d, J= 8.7 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1H), 7.90-8.00 (m, 3H), 8.07 (s, 1H), 8.14 (d, J= 7.2 Hz, 1H), 8.64 (s, 1H), 9.26 (s, 1H). MS (ES+): 171/Z 606 (M+H)+.
EXAMPLE 87. 5-Methyl-N2-13-(4-methyl-piperazine-1-sulfonv1)-phenyll-pyrimidine-2,4-diamine (Intermediate 351 nit H2 N N
[0198] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(4-methyl-piperazine-1-sulfony1)-phenylamine (0.50 g, 2.0 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C
for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to ¨9 with 10% NaOH
solution. The resulting solution was extracted with Et0Ac (2 x 30 mL) and the organic layer separated.
The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product (-0.42 g) used in the next step without purification. MS (ES+): m/z 363 (M+H)+.
EXAMPLE 88. N-tert-Buty1-345-methyl-243-(4-methyl-piperazine-1-sulfony1)-phenylaminol-pyrimidin-4-ylarninol-benzenesulfonamide (Compound LV) Ho >N 101 ,A
NH
N-40) N N
LV
[0199] A suspension of intermediate 35 (0.10 g, 0.28 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (80 mg, 0.27 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue dissolved in minimum amount of Et0Ae and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (10 mg, 6%).
[0200] 1H NMR (500 MHz, DMSO-d6): 5 1.12 (s, 9H), 2.13 (s, 3H), 2.16 (s, 3H), 2.33-2.40 (m, 4H), 2.85-2.94 (m, 4H), 7.18 (d, J= 8.1 Hz, 1H), 7.44 (t, J= 8.0 Hz, 1H), 7.49-7.54 (m, 2H), 7.58 (s, 1H), 8.00-8.03 (m, 2H), 8.13 (s, 1H), 8.15 (dd, J= 8.6, 1.6 Hz, 1H), 8.18-8.23 (m, 1H), 8.66 (s, 1H), 9.38 (s, 1H). MS (ES+): m/z 574 (M+H)+.
EXAMPLE 89. N-tert-Buty1-345-methy1-2-(4-piperazin-1-ylmethyl-phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LVI) Ho N
NH
NN NH
LVI
[0201] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-amino-benzy1)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.34 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.20g, 0.61 mmol) in dioxane/DMF
(3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C
for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was dissolved in DCM (6 mL) and TFA (3 mL) added. The mixture was stirred at room temperature for lh, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid triturated in hexanes/Et0Ac (10/1, 55 mL). After filtration, the title compound was obtained as a white solid (32 mg, 22%).
[0202] NMR (500 MHz, DMSO-d6): 61.12 (s, 9H), 2.13 (s, 3H), 2.30-2.40 (m, 4H), 2.85 (t, J= 4.7 Hz, 4H), 3.38 (s, 2H), 7.09 (d, J= 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1H), 7.59 (d, J= 8.5 Hz, 2H), 7.94 (s, 1H), 8.10 (s, 1H), 8.13-8.16 (m, 1H), 8.59 (s, 1H), 8.96 (s, 1H). MS (ES+): mtz 510 (M+H)+.
EXAMPLE 90. N-tert-Buty1-3-{5-methy1-2-1-4-(2-pyrrolidin-l-yl-ethoxy)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LVII) H
>Nic);N
NH
N
N N
LVII
[0203] A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).
[0204] IHNMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J= 5.8 Hz, 2H), 3.99 (t, J= 6.0 Hz, 2H), 6.79 (d, J= 9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H).
MS (ES+): nilz 525 (M+H)+.
EXAMPLE 91. 3-15-Methv1-2-[444-methyl-piperazin-1-y1)-phenylamino]-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LVIII) H2N.C?
NH
8 N) kN)N
LVIII
[0205] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-benzenesulfonamide (0.10 g, 0.42 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC.
The fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a grey solid (10 mg, 7%).
[0206] 1H NMR (500 MHz, DMSO-d6): 8 2.10 (s, 3H), 2.22 (s, 3H), 2.44 (t, J=
4.9 Hz, 4H), 3.03 (t, J= 4.9 Hz, 4H), 6.81 (d, J= 9.0 Hz, 2H), 7.34 (s, 2H), 7.45-7.50 (m, 4H), 7.89 (s, 1H), 8.06 (s, 1H), 8.13-8.18 (m, 1H), 8.54 (s, 1H), 8.70 (s, 1H). MS
(ES+): m/z 454 (M+H)+.
EXAMPLE 92. N-Methy1-3-15-methyl-2-[4-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LIX) Ho 1.1 NH
8 ,õ7-LN
I
N
LIX
[0207] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N-methyl-benzenesulfonamide (0.11 g, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and in-adiated with microwave at 160 C
for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of DCM/Et20 (1/5, 30 mL).
After filtration, the title compound was obtained as a light brown solid (65 mg, 42%).
[0208] IHNMR. (500 MHz, DMSO-d6): 5 2.11 (s, 3H), 2.23 (s, 3H), 2.44 (d, J
5.0 Hz, 3H), 2.45-2.50 (m, 4H), 3.03 (t, J= 4.9 Hz, 4H), 6.81 (d, J= 9.1 Hz, 2H), 7.40-7.43 (m, 2H), 7.46 (d, J= 9.1 Hz, 2H), 7.52 (t, J= 8.0 Hz, 1H), 7.89 (s, 1H), 7.94 (t, J=
1.8 Hz, 1H), 8.29 (br d, J= 8.3 Hz, 1H), 8.56 (s, 1H), 8.72 (s, 1H). MS (ES+): m/z 468 (M+H)+.
EXAMPLE 93. N,N-Dimethy1-3-{5-methyl-2-[4-(4-methyl-piperazin-1-y1)-phenylaminol-pyrirnidin-4-ylaminol-benzenesulfonamide (Compound LX) lo= el N
NH
N
LX
[0209] A suspension of intemiediate 32 (0.13 g, 0.43 mmol), 3-bromo-N,N-dimethy1-benzenesulfonamide (0.14 g, 0.53 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.33 g, 1.0 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture ofEt0Ac/hexanes (1/5, 30 mL). After filtration, the title compound was obtained as an off white solid (60 mg, 29%).
[0210] 1H NMR (500 MHz, DMSO-d6): 8 2.17 (s, 3H), 2.23 (s, 3H), 2.44 (d, J=
5.0 Hz, 3H), 2.45-2.50 (m, 4H), 2.63 (s, 6H), 3.03 (t, J= 4.9 Hz, 4H), 6.81 (d, J= 9.1 Hz, 2H), 7.36 (d, J¨ 8.0 Hz, 1H), 7.45 (d, J= 9.1 Hz, 2H), 7.54 (t, J= 8.0 Hz, 1H), 7.84 (t, J= 1.9 Hz, 1H), 7.90 (s, 1H), 8.46 (br d, J= 7.8 Hz, 1H), 8.57 (s, 1H), 8.74 (s, 1H). MS
(ES+): m/z 482 (M+H)+ .
EXAMPLE 94. N-Isopropy1-3-{5-methy1-2-14-(4-methyl-piperazin-1-yI)-phenylamino)-pyrimidin-4-ylamino)-benzenesulfonamide (Compound LXI) NH
ON
tNN
LXI
[0211] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N-isopropyl-benzenesulfonamide (0.11 g, 0.39 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as an off white solid (47 mg, 29%).
[0212] 1H NMR (500 MHz, DMSO-d6): 60.98 (d, J= 6.6 Hz, 6H), 2.11 (s, 3H), 2.24 (s, 3H), 2.45-2.50 (m, 4H), 3.03 (t, J= 4.8 Hz, 4H), 3.20-3.27 (m, 1H), 6.80 (d, J= 9.0 Hz, 2H), 7.40-7.52 (m, 4H), 7.59 (d, J= 7.1 Hz, 1H), 7.89 (s, 1H), 8.21 (br d, J= 7.9 Hz, 1H), 8.53 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 496 (M+H)+.
EXAMPLE 95. Ar4-(3-Methanesulfonv1-4-methyl-pheny1)-5-methyl-N2-14-(4-methyl-piperazin-1-y1)-phenyll-p_yrimidine-2,4-diamine (Compound LXII) y=
NH rThe I
N
LXII
[0213] A suspension of inteimediate 32 (0.10 g, 0.33 mmol), 4-bromo-2-methanesulfonyl-1-methyl-benzene (0.10 g, 0.40 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/5, 30 mL). After filtration, the title compound was obtained as a light brown solid (41 mg, 27%).
[0214] 111 NMR (500 MHz, DMSO-d6): 8 2.09 (s, 3H), 2.22 (s, 3H), 2.45 (t, J= 4.7 Hz, 4H), 2.61 (s, 3H), 3.03 (t, J= 4.9 Hz, 4H), 3.20 (s, 3H), 6.80 (d, J= 9.1 Hz, 2H), 7.35 (d, J=
8.5 Hz, 1H), 7.44 (d, J= 9.0 Hz, 2H), 7.87 (s, 1H), 8.05 (d, J¨ 2.4 Hz, 1H), 8.21 (br d, J-7 .0 Hz, 1H), 8.55 (s, 1H), 8.71 (s, 1H). MS (ES+): nilz 467 (M+H) .
EXAMPLE 96. N-Cyclohexy1-3-{5-methy1-244-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylamino}-benzenesulfonamide (Compound LXIH) r-.Nr (1,`
NH
LJON
tNI*
LXIII
[02151 A suspension of intermediate 32 (0.10 g, 0,33 mmol), 3-bromo-N-cyclohexyl-benzenesulfonamide (0.13 g, 0.41 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as an off white solid (45 mg, 25%).
[02161 1H NMR (500 MHz, DMSO-d6): 6 1.07-1.17 (m, 6H), 1.53-1.63 (m, 4H), 2.11 (s, 3H), 2.22 (s, 3H), 2.45 (t, J= 4.7 Hz, 4H), 2.90-3.00 (in, 1H), 3.02 (t, J=
4.8 Hz, 4H), 6.80 (d, J= 9.1 Hz, 2H), 7.43-7.53 (m, 4H), 7.65 (d, J= 7.3 Hz, 1H), 7.89 (s, 1H), 8.05 (s, 1H), 8.18 (br d, J= 7.7 Hz, 1H), 8.52 (s, 1H), 8.71 (s, 1H). MS (ES+): nilz 536 (M+H)+.
EXAMPLE 97. N,N-Diethy1-3-15-methyl-2-[444-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LXIV) == I.
NH
I
N
LXIV
[02171 A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N,N-diethyl-benzenesulfonamide (0.12 g, 0.41 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as an off white solid (45 mg, 27%).
[0218] 1H NMR (500 MHz, DMSO-d6): 5 1.06 (t, J= 7.1 Hz, 6H), 2.11 (s, 3H), 2.22 (s, 3H), 2.44 (t, J= 4.7 Hz, 4H), 3.03 (t, J= 4.8 Hz, 4H), 3.16 (q, J= 7.1 Hz, 4H), 6.80 (d, J=
9.1 Hz, 2H), 7.39 (d, J= 8.1 Hz, 1H), 7.45 (d, J= 9.0 Hz, 2H), 7.50 (t, J= 8.1 Hz, 1H), 7.89 (t, J= 1.9 Hz, 1H), 7.89 (s, 1H), 8.39 (br d, J= 7.9 Hz, 1H), 8.53 (s, 1H), 8.74 (s, 1H). MS
(ES+): nilz 510 (M+H)+.
EXAMPLE 98. 5-Methyl-N2-1444-methyl-piperazin-1-y1)-pheny11-/V4-(3-(morpholine-sulfony1)-phenyll-pyrimidine-2,4-diamine (Compound LXV) ,Ii 0 e N l NH
N
N
LXV
[0219] A suspension of inteimediate 32 (0.10 g, 0.33 mmol), 4-(3-bromo-benzenesulfony1)-morpholine (0.12 g, 0.39 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF
(3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as a light red solid (90 mg, 52%).
[0220] 1H NMR (500 MHz, DMSO-d6): 5 2.12 (s, 3H), 2.22 (s, 3H), 2.45 (t, J=
4.8 Hz, 4H), 2.89 (t, J= 4.6 Hz, 4H), 3.03 (t, J= 4.8 Hz, 4H), 3.64 (t, J= 4.7 Hz, 4H), 6.81 (d, J=
9.1 Hz, 2H), 7.35 (d, J= 8.1 Hz, 1H), 7.45 (d, J= 9.0 Hz, 2H), 7.56 (t, J= 8.1 Hz, 1H), 7.84 (t, J= 1.9 Hz, 1H), 7.91 (s, 1H), 8.47 (br d, J= 8.4 Hz, 1H), 8.59 (s, 1H), 8.75 (s, 1H). MS
(ES+): m/z 524 (M+H)+.
EXAMPLE 99. 3-{5-Methyl-2-44-(4-methyl-piperazin-1-y1)-phenylamino[-pyrimidin-ylaminol-benzoic acid ethyl ester (Intermediate 36) Et0 NH
I
N
[0221] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-benzoic acid ethyl ester (0.07 mL, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 10% Me0H/DCM) to afford the title compound (0.10 g, 68%). MS (ES+): in/z 447 (M+H)+.
EXAMPLE 100. 3-15-Methyl-2-14-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzamide (Compound LXVI) NH N-N
tNN
LXVI
[0222] A mixture of intermediate 36 (0.10 g, 0.22 mmol) in concentrated NH4OH
was sealed in a reaction tube and heated at 50 C for 3 d. The mixture was poured into water (15 mL) and extracted with Et0Ac (2 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2504 and filtered.
The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as a white solid (10 mg, 11%).
[0223] 1H NMR (500 MHz, DMSO-d6): 6 2.10 (s, 3H), 2.22 (s, 3H), 2.40-2.50 (m, 4H), 2.95-3.05 (m, 4H), 6.75 (d, J= 9.1 Hz, 2H), 7.30-7.40 (in, 2H), 7.45 (d, J=
9.1 Hz, 2H), 7.53-7.58 (m, 1H), 7.85 (s, 1H), 7.90 (br s, 2H), 8.03 (s, 1H), 8.37 (s, 1H), 8.71 (s, 1H). MS
(ES+): nilz 418 (M+H)+.
EXAMPLE 101. 2-Methyl-3-{5-methyl-2-14-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-y1aminol-benzoic acid ethyl ester (Compound LXVII1 0 0 Et Nõ N
NNS
LXVII
[0224] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-2-methyl-benzoic acid ethyl ester (0.10 mL, 0.41 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% Me0H and 1% TEA in DCM) to afford the title compound (0.14 g, 92%) as a light brown oil.
[0225] 1H NMR (500 MHz, DMSO-d6): 6 1.32 (t, J= 7.1 Hz, 3H), 2.10 (s, 3H), 2.21 (s, 3H), 2.32 (s, 3H), 2.40-2.45 (m, 4H), 2.94 (t, J= 4.8 Hz, 4H), 4.30 (q, J= 7.1 Hz, 2H), 6.57 (d, J= 9.1 Hz, 2H), 7.25 (d, J= 8.9 Hz, 2H), 7.35 (t, J= 7.8 Hz, 1H), 7.48 (dd, J= 7.9, 1.0 Hz, 1H), 7.70 (dd, J= 7.8, 1.1 Hz, 1H), 7.78 (s, 1H), 8.23 (s, 1H), 8.58 (s, 1H). MS (ES+):
nilz 461 (M+H)+.
EXAMPLE 102. 2-Methy1-3-15-methy1-2-[4-(4-methyl-piperazin-1-y1)-phenylamino]-pyrimidin-4-ylaminol-benzamide (Compound LXVIII) le NH
NN
LXVIII
[0226] To a mixture of the above-described compound LXVII (0.10 g, 0.22 mmol) and formamide (0.05 mL, 1.3 mmol) in DMF (5 mL) at 100 C was added Na0Me (0.10 g, 0.46 mmol) under the argon atmosphere. The mixture was stirred at the same temperature for 2 h and then at room temperature for additional 15 h. The mixture was poured into water (15 mL) and extracted with Et0Ac (2 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/5, 30 mL). After filtration, the title compound was obtained as a white solid (20 mg, 21%).
[0227] NMR (500 MHz, DMSO-d6): 8 2.09 (s, 3H), 2.21 (s, 3H), 2.23 (s, 3H), 2.40-2.45 (m, 4H), 2.97 (t, J= 4.8 Hz, 4H), 6.69 (d, J= 9.1 Hz, 2H), 7.24-7.28 (m, 2H), 7.35 (d, J= 9.0 Hz, 2H), 7.39-7.43 (m, 2H), 7.69 (s, 1H), 7.78 (s, 1H), 8.01 (s, 1H), 8.53 (s, 1H). MS (ES+):
m/z 432 (M+H)+.
EXAMPLE 103. (2-Chloro-5-methyl-pyrimidin-4-y1)-(4-ehloro-3-trifluoromethyl-pheny1)-amine (Intermediate 37) CI si \)k-.
CI
[0228] A mixture of 2-ehloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), bromo-1-chloro-2-trifluoromethyl-benzene (0.40 mL, 2.7 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.22 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in dioxane/DMF (6/1, 7 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 50%
Et0Ae/hexanes) to afford the title compound (0.65 g, 96%) as a white solid. MS
(ES+): rth 322 (M+H)+.
EXAMPLE 104. N4-(4-Ch1oro-3-trifluoromethy1-pheny1)-5-methy1-N2-1.4-(piperidin-yloxy)-phenyll-pyrimidine-2,4-diamine (Compound LXIX) CI
akt N NH
LXIX
[0229] A mixture of intermediate 37 (0.10 g, 0.31 mmol) and 4-(4-amino-phenoxy)-piperidine-1-earboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C
for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and neutralized with 10% NaOH solution until solid precipitated. The resulting solid was filtered and purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a white solid (30 mg, 20%).
[0230] 1H
NMR (500 MHz, DMSO-d6): 8 1.69-1.77 (in, 2H), 2.00-2.04 (m, 2H), 2.11 (s, 3H), 2.90-3.00 (in, 2H), 3.10-3.20 (in, 2H), 4.40-4.48 (in, 1H), 6.84 (d, J=
9.0 Hz, 2H), 7.49 (d, J= 9.0 Hz, 2H), 7.58 (d, J= 8.8 Hz, 1H), 7.94 (s, 1H), 8.12 (d, J= 2.6 Hz, 1H), 8.21 (br d, J= 8.2 Hz, 1H), 8.64 (s, 1H), 8.93 (s, 1H). MS (ES+): m/z 478 (M+H)+.
EXAMPLE 105. 5-Methyl-N2-14-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Intermediate 38) ' NN
[0231] A
mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (1.1 g, 5.3 mmol) in acetic acid (8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH ¨10.
The resulting aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a grey solid (0.80 g, 73%). It was used in the next step without purification. MS (ES+): m/z 314 (M+H)+.
EXAMPLE 106. 3-45-Methy1-2-14-(2-pyrrolidin-1-yl-ethoxy)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LXX), H2N,9 N
LXX
[0232] A mixture of intermediate 38 (0.10 g, 0.32 mmol), 3-bromo-benzenesulfonamide (0.10 g, 0.42 rnmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 25 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and solid triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as a white solid (11 mg, 7%).
[0233] 111 NMR (500 MHz, DMSO-d6): 8 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.49-2.52 (m, 4H), 2.75-2.80 (m, 2H), 4.00 (t, J = 5.9 Hz, 2H), 6.80 (d, J= 9.0 Hz, 2H), 7.34 (s, 2H), 7.45-7.50 (m, 2H), 7.52 (d, J 9.0 Hz, 2H), 7.90 (s, 1H), 8.05 (s, 1H), 8.10-8.15 (m, 1H), 8.57 (s, 1H), 8.77 (s, 1H). MS (ES+): inlz 469 (M+H)+.
EXAMPLE 107. 5-Methyl-N2-(4-morpholin-4-vImethyl-nhenv1)-pyrimidine-2,4-diamine (Intermediate 39) N.)N
[0234] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.40 g, 2.8 mmol) and 4-morpholin-4-ylmethyl-phenylamine (0.60 g, 3.1 mmol) in acetic acid (15 mL) was heated at 70 C for 17 h. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH ¨10.
The resulting aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a brown syrup (0.70 g, 83%). It was used in the next step without purification. MS (ES+): nilz 300 (M+H)+
EXAMPLE 108 M-(1H-Indo1-4-y1)-5-methyl-N2-(4-morpholin-4-ylmethyl-pheny1)-pyrimidine-2,4-diamine (Compound UM) HN
411) NH
NiLN c0 "XXI
[0235] A mixture of intetmediate 39 (0.40 g, 1.3 mmol), 4-bromo-1-triisopropylsilanyl-1H-indole (0.50 g, 1.4 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (0.90 g, 2.8 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to Et0Ac) to afford the TIPS protected precursor as a yellow oil.
[0236] To the above TIPS protected precursor (50 mg, 0.088 mmol) in THF (5 mL) was added TBAF (0.5 mL, 1M in THF). The mixture was stirred at room temperature for 1 h and then poured into water (20 mL). The aqueous layer was extracted with Et0Ac (2 x 20 mL) and the combined organic layers washed With brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and solid dissolved in minimum amount of Et0Ac and then hexanes added until solid precipitated.
After filtration, the title compound was obtained as a light brown solid (6 mg, 1% overall yield).
[0237] 1H NMR (500 MHz, DMSO-d6): 62.17 (s, 3H), 2.25-2.30 (m, 4H), 3.29 (s, 2H), 3.54 (t, J= 4.5 Hz, 4H), 6.40 (t, J= 2.2 Hz, 1H), 6.89 (d, J= 8.5 Hz, 2H), 7.09 (t, J= 7.8 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.27 (t, J= 2.8 Hz, 1H), 7.30 (d, J= 7.5 Hz, 1H), 7.43 (d, Jr 8.5 Hz, 2H), 7.85 (s, 1H), 8.14 (s, 1H), 8.77 (s, 1H), 11.10 (s, 1H). MS
(ES+): nilz 415 (M+H)+ .
EXAMPLE 109. 4-1-4-(4-Amino-5-methyl-pyrimidin-2-ylamino)-benzyl[-piperazine-1-= carboxylic acid tert-butyl ester (Intermediate 40) N`
N
N N
40 Boc [0238] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.35 g, 2.4 mmol) and 4-(4-amino-benzy1)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 2.8 mmol) in acetic acid (20 inL) was heated at 70 C for 1 d. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10%
NaOH
solution until pH ¨10. The resulting aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the title compound used in the next step without purification. MS (ES+): nz/z 399 (M+H) .
EXAMPLE 110. 10-(1H-Indo1-4-y1)-5-methyl-N2-(4-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine (Compound LXXII) HN \
N N') N*N NH
DOCII
[0239] A mixture of intermediate 40 (0.78 g, 2.0 mmol), 4-bromo-1 -triisopropylsilanyl-1H-indole (0.70 g, 2.0 mmol), Pd2(dba)3 (0.15 g, 0.16 mmol), Xantphos (0.19 g, 0.32 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4.5 h. The reaction mixture was cooled to room temperature, filtered and the filtered solid was with DCM (30 mL). The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 30%
Et0Ac/hexanes) to afford the TIPS protected precursor.
[0240] To the above TIPS protected precursor (0.10 g, 0.15 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and solid triturated in a mixture of Et0Ac/hexanes (1/5, 30 mL). After filtrationõ the title compound was obtained as a white solid (25 mg, 3% overall yield).
[0241] 1H NMR (500 MHz, DMSO-d6): 8 2.17 (s, 3H), 2.20-2.30 (m, 4H), 2.73 (t, J= 4.6 Hz, 4H), 3.28 (s, 2H), 6.41 (t, J= 2.2 Hz, 1H), 6.89 (d, J= 8.5 Hz, 2H), 7.09 (t, J= 7.8 Hz, 1H), 7.24 (d, J= 8.3 Hz, 1H), 7.27 (t, J= 2.8 Hz, 1H), 7.31 (d, J= 7.5 Hz, 1H), 7.44 (d, J=
8.5 Hz, 2H), 7.85 (s, 1H), 8.13 (s, 1H), 8.77 (s, 1H), 11.10 (s, 1H) MS (ES+): 7n/z 414 (M+H)+, EXAMPLE 111. 5-Methyl-N4-(7-methy1-1H-indo1-4-y1)-N2-(4-(4-methylpiperazin-1-y1)phenyl) pyrimidine-2,4-diamine (Compound LXXIII) NH
H N
.1 N 401 N
N
LXXIII
[0242] A mixture of intermediate 32 (674 mg, 2.25 mmol), 4-bromo-7-methyl-1H-indole (522 mg, 2.48 mmol), Pd2(dba)3 (182 mg, 0.2 mmol), Xantphos (360 mg, 0.6 mmol) and cesium carbonate (2.6 g, 8 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (136 mg of HC1 salt, 13%) as a white solid.
[0243] 1H NMR (500 MHz, DMSO-d6): 8 2.21 (s, 3H), 2.55 (s, 3H), 2.80 (d, J=
4.6 Hz, 3H), 3.00-3.05 (m, 2H), 3.10-3.16 (m, 2H), 3.45-3.48 (in, 2H), 3.64-3.66 (in, 2H), 6.33-6.34 (m, 1H), 6.63 (br, 2H), 6.92-6.97 (in, 4H), 7.35 (t, J= 2.7 Hz, 1H), 7.83 (s, 1H), 10.04 (s, 1H), 10.24 (s, 1H), 11.08 (br s, 1H), 11.34 (s, 1H), 12.12 (br s, 1H). MS
(ES+): m/z 428 (M+H)+.
EXAMPLE 112. N4-(7-Chloro-11/-indo1-4-y1)-5-methyl-N2-(4-(4-methylpiperazin-1-yl)phenyl) pyrimidine-2,4-diamine (Compound LXXIV1 / NH
Cl HN
N
DOCIV
[0244] A mixture of intemiediate 32 (298 mg, 1.0 mmol), 4-bromo-7-chloro-1H-indole (231 mg, 1.04 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (251 mg of HC1 salt, 51%) as a white solid.
[0245] 1H NMR (500 MHz, DMSO-d6): 8 2.21 (s, 3H), 2.80 (d, J= 4.6 Hz, 3H), 3.01-3.05 (m, 2H), 3.08-3.13 (m, 2H), 3.46-3.48 (m, 2H), 3.65-3.67 (m, 2H), 6.46-6.47 (m, 1H), 6.64 (br s, 1H), 6.93 (d, J= 8.9 Hz, 2H), 7.05 (d, J= 8.1 Hz, 2H), 7.25 (d, J= 8.0 Hz, 2H), 7.43-7.44 (m, 1H), 7.87 (s, 1H), 10.13 (s, 1H), 10.27 (s, 1H), 11.00 (br s, 1H), 11.70 (s, 1H), 12.23 (br s, H). MS (ES+): m/z 448 (M+H)+.
EXAMPLE 113. N2-(4-(2-(Pyrrolidin-1-ybethoxy)pheny11-5-methyl-N4-(7-methyl-1H-indol-4-y1) pyrimidine-2,4-diamine (Compound LXXV1 /NH
HN
0,No DON
[0246] A mixture of intermediate 38 (410 mg, 1.3 mmol), 4-bromo-7-methyl-1H-indole (275 mg, 1.3 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo.
The residue was purified by HPLC to afford the title compound (92 mg of HC1 salt, 15%) as a white solid.
[0247] 1H NMR (500 MHz, DMSO-d6): 6 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21 (s, 3H), 2.55 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.54 (m, 4H), 4.26 (t, J= 4.9 Hz, 2H), 6.33-6.34 (m, 1H), 6.61 (br d, 2H), 6.93-6.95 (m, 2H), 7.03 (d, J= 8.9 Hz, 2H), 7.34 (t, J= 2.8 Hz, 1H), 7.85 (s, 1H), 10.07 (s, 1H), 10.33 (s, 1H), 10.91 (br s, 1H), 11.34 (s, 1H), 12.15 (br s, H). MS
(ES+): m/z 443 (M+H)+.
EXAMPLE 114. N2-(4-(2-(Pyrrolidin-1-ybethoxy)pheny1)-5-methyl-N447-ehloro-1H-indol-4-y1) pyrimidine-2,4-diamine (Compound LXXVI) NH
ei CI
HN
()NOI I
NN
LLXVI
[0248] A mixture of intefinediate 38 (270 mg, 0.86 mmol), 4-bromo-7-chloro-1H-indole (198 mg, 0.86 mmol), Pd2(dba)3 (72 mg, 0.08 mmol), Xantphos (140 mg, 0.24 mmol) and cesium carbonate (1.3 g, 4 nu-nol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue Was purified by HPLC to afford the title compound (33 mg of HC1 salt, 8%) as a white solid.
[0249] 1H NMR (500 MHz, DMSO-d6): 8 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.22 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.54 (in, 4H), 4.27 (t, J= 4.9 Hz, 2H), 6.46-6.47 (m, 1H), 6.63 (br d, 2H), 6.95 (d, J= 8.2 Hz, 2H), 7.06 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.43 (t, J= 2.8 Hz, 1H), 7.90 (s, 1H), 10.13 (s, 1H), 10.40 (s, 1H), 10.94 (br s, 1H), 11.70 (s, 1H), 12.33 (br s, H). MS (ES+): m/z 463 (M+H)+.
EXAMPLE 115. N2-(4-(2-(Pyrrolidin-1-yflethoxy)pheny1)-5-methyl-/V4-(7-fluoro-indol-4-y1) pyrimidine-2,4-diamine (Compound LXXVII) NH
F
H N
.t ONo N N
UOCVII
[0250] A mixture of intermediate 38 (413 mg, 1.3 mmol), 4-bromo-7-fluoro-1H-indole (310 mg, 1.45 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (10 mg of HC1 salt, 1.5%) as a brown solid.
[0251] 1H NMR (500 MHz, DMSO-d6): 8 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.56 (m, 4H), 4.26 (t, J= 4.9 Hz, 2H), 6.42-6.43 (m, 1H), 6.63 (br d, 2H), 6.95-7.04 (m, 3H), 7.35 (d, J= 8.9 Hz, 1H), 7.42 (t, J= 2.8 Hz, 1H), 7.89 (s, 1H), 10.08 (s, 1H), 10.41 (s, 1H), 10.90 (br s, 1H), 11.85 (s, 1H), 12.33 (br s, H). MS (ES+): m/z 447 (M+H)+.
EXAMPLE 116. N4-(3-tert-Butylpheny1)-5-methyl-N244-(4-methylpiperazin-1-14)Phenvbffrimidine-2,4-diamine (Compound UOCVIII) HN
NN) N
=N
LXXVIII
[0252] A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-tert-buty1-3-bromobenzene (256 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo.
The residue was purified by HPLC to afford the title compound (27 mg of HC1 salt, 6%) as a white solid.
[0253] 1H NMR (500 MHz, DMSO-d6): 5 1.25 (s, 9H), 2.16 (s, 3H), 2.80 (d, J=
4.6 Hz, 3H), 3.04-3.16 (m, 4H), 3.47-3.49 (m, 211), 3.65-3.67 (m, 211), 6.90 (d, J= 8.9 Hz, 2H), 7.26 (d, J
9.0 Hz, 2H), 7.28-7.35 (m, 2H), 7.45 (t, J= 1.8 Hz, 1H), 7.50 (d, J= 7.8 Hz, 1H), 7.86 (s, 111), 9.70 (s, 1H), 10.37 (s, 1H), 11.01 (br s, 111), 12.34 (br s, H). MS
(ES+): nilz 431.
(M+H)+.
EXAMPLE 117. N-(3-tert-ButylphenyI)-2-ehloro-5-methylpyrimidin-4-amine (Intermediate 41) 1.1 HN
I
CI
[0254] A mixture of 2-chloro-5-methylpyrimidin-4-amine (670 mg, 4.7 mmol), 1-tert-butyl-3-bromobenzene (1.5 g, 7 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), Xantphos (695 mg, 1.2 mmol) and cesium carbonate (6.2 g, 19 mmol) was suspended in dioxane (150 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacua The residue was dissolved in Et0Ac (10 mL) and added hexanes (100 mL). The solid was collected by filtration and washed with hexanes to afford the crude title compound (1.2 g, 99%) as a yellow solid.
EXAMPLE 118. N4-(3-tert-Butylpheny1)-5-methyl-N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (Compound LXXIX) HN
\) 0 11 ei --CNH
1\17 N
LXXIX
[0255] A mixture of intermediate 41 (740 mg, 2.68 mmol) and tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (500 mg, 1.71 mmol) was suspended in acetic acid (10 mL) and heated at 100 C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (276 mg of HC1 salt, 35%) as a yellow solid.
[0256] 1H NMR (500 MHz, DMSO-d6): 8 1.22 (s, 9H), 1.77-1.81 (m, 2H), 2.03-2.07 (m, 2H), 2.14 (s, 3H), 3.00-3.04 (m, 2H), 3.18 (br s, 2H), 4.56-4.57 (m, 1H), 6.86 (d, J= 8.9 Hz, 2H), 7.26-7.31 (m, 4H), 7.40 (s, 1H), 7.44 (d, J= 7.5 Hz, 1H), 7.84 (s, 1H), 8.93 (br s, 1H), 8.99 (br s, 1H), 9.67 (s, 1H), 10.31 (s, 1H). MS (ES+): nz/z 432 (M+H)+.
EXAMPLE 119. tert-Butyl 444-(4-amino-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-carboxylate (Intermediate 42) o Iei --CNBoc N
[0257] A mixture of 2-chloro-5-methylpyrimidin-4-amine (540 mg, 3.7 mmol), tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (1.1 g, 3.7 mmol) was suspended in acetic acid (20 mL) and heated at 70 C for 1 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 nit) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacua to afford the title compound (1.4 g, 95%) as a yellow solid.
EXAMPLE 120. /V4-(1H-Indazol-4-y1)-5-methyl-N244-(piperidin-4-y1oxy)pheny1)pyrimidine-24-diamine (Compound LXXX) N-NH
HN
= I O-CNH
LXXX
[0258] A mixture of intermediate 42 (480 mg, 1.2 mmol), 4-bromo-1H-indazole (236 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol). was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo.
The residue was purified by HPLC to afford the title compound (4 mg of HC1 salt, 1.2%) as a yellow solid.
[0259] 1H NMR (500 MHz, DMSO-d6): 6 1.75-1.80 (m, 2H), 2.02-2.07 (m, 2H), 2.24 (s, 3H), 3.05-3.09 (m, 2H), 3.17-3.21 (m, 2H), 4.52 (br s, 1H), 6.63 (d, J= 8.6 Hz, 2H), 7.01 (d, J= 8.6 Hz, 2H), 7.14 (d, J= 7.3 Hz, 2H), 7.38-7.44 (m, 2H), 7.62 (d, J= 8.9 Hz, 2H), 7.92 (s, 1H), 8.02 (s, 1H), 9.00 (br s, 1H), 9.04 (br s, 1H), 10.20 (s, 1H), 10.33 (s, 1H). MS (ES+):
nz/z 416 (M+H)+.
EXAMPLE 121. 4-{3-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-71amino -benz 1 - 1 ester Intermediate 43 CI ip \/
N 410 ri\I 0 N
[0260] A mixture of intermediate 31 (0.092 g, 0.33 mmol), 4-(3-amino-benzy1)-piperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.39 mmol), Pd2(dba)3 (0.03 g, 0.033 mmol), Xantphos (0.038 g, 0.065 mmol) and cesium carbonate (0.32 g, 0.98 mmol) was suspended in dioxane (5 mL) and microwaved at 160 C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.075 g, 43%) as a brown solid.
EXAMPLE 122. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(3-piperazin-l-Vimethyl-pheny1)-pvrimidine-2,4-diamMe (Compound LXXXI) CI lp NH
NN
N
NH
LXXXI
[0261] A solution of intermediate 43 (0.075 g, 0.14 mmol) in DCM (8 mL) was treated with TFA (2 mL). After 2 h of stirring, solvents were removed and resulting residue was triturated with diethyl ether resulting in white hygroscopic powder (0.05 g, 82%).
[0262] IFT NMR (500 MHz, DMSO-d6): 8 2.17 (s, 3H), 2.89 (br s, 4H), 3.2 (br s, 4H), 3.68 (s, 4H), 3.82 (br s, 3H), 7.16-7.19 (m, 2H), 7.28 (t, J= 7.9 Hz, 1H), 7.33 (d, J= 2.3 Hz, 1H), 7.39 (s, 1H), 7.43 (d, J= 8.5 Hz, 1H), 7.49 (d, 8.6 Hz, 1H), 7.98 (s, 1H), 8.8 (br s, 2H), 9.78 (br s, 1H), 10.57 (br s, 1H). MS (ES+): m/z 439 (M+H)+.
EXAMPLE 123. /V4-(4-Chlor0-3-methoxy-pheny1)-5-methyl-N244-(piperidin-4-yloxY)-pheny1]-pyrimidine-2,4-diamineiCompound LXXXII) Cl (3 N N
LXXXII
[0263] A mixture of intermediate 31 (0.66 g, 2.3 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.88 mg, 3.0 mmol) in acetic acid (15 mL) was microwaved at 160 C for 15 min. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated.
Filtration followed by column chromatography yielded the title compound as beige solids (0.51 g, 50%).
[0264] 1H NMR (500 MHz, DMSO-d6): 8 1.37-1.44 (m, 2H), 1.86-1.89 (m, 2H), 2.09 (s, 3H), 2.50-2.56 (m, 2H), 2.91-2.95 (m, 2H), 3.16 (s, 3H), 3.32 (br s, 3H), 3.72 (s, 3H), 4.09 (br s, 1H), 4.21-4.26 (m, 1H), 6.77 (d, J= 9 Hz, 2H), 7.27 (d, J = 8.5 Hz, 1H), 7.40-7.42 (in, 1H), 7.46-7.49 (m, 3H), 7.87 (s, 1H), 8.31 (s, 1H), 8.78 (s, 1H). MS (ES+):
in/z 440 (M+H)+.
EXAMPLE 124. 4-{34444-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-=
ylaminol-phenyll-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 44) Cl le NH
H NO
N N
[0265] A mixture of inteimediate 31 (0.13 g, 0.46 mmol) and 4-(3-amino-pheny1)-piperazine-l-carboxylic acid tert-butyl ester (0.19 mg, 0.68 mmol) in acetic acid (8 mL) was heated at 80 C for 15 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken up in water (20 mL) and the mixture was neutralized with 10% NaOH solution. This was then extracted with ethyl acetate, washed with brine and evaporated to oily residue. Column chromatography yielded =
the title compound as white solids (0.12 g, 48%).
EXAMPLE 125. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(3-piperazin-1-y1-pheny1)-pyrimidine-2,4-diamine (Compound LXXXIII1 CI op N
N N NLXXXIII
NH
[0266] A solution of intermediate 44 (0.11 g, 0.21 mmol) in DCM (8 mL) was treated with TFA (1 mL). After 3 h of stirring, solvents were removed and resulting residue was taken up in ethyl acetate and washed with 10% sodium bicarbonate solution.
Organic phase then dried over sodium sulfate, filtered and evaporated to white powder. This was diluted with DCM (5 mL) and treated with 4M HC1 in dioxane (0.5 mL). Solvents were imediately removed affording HCL salt of title compound as white solids (0.06 g, 67%).
[0267] 1H NMR (500 MHz, DMSO-d6): 8 2.18 (s, 3H), 3.12 (hr s, 4H), 3.22 (hr s, 4H), 3.65 (s, 3H), 6.80 (d, J= 8.1 Hz, 1H), 6.95 (s, 2H), 7.14 (t, J= 8.2 Hz, 1H), 7.23 (d, J= 7.0 Hz, 1H), 7.37-7.40 (m, 2H), 7.95 (s, 1H), 9.33 (hr s,-2H), 9.88 (s; 1H), 10.62 (s, 1H). MS
(ES+): m/z 425 (M+H)+.
EXAMPLE 126. 244-(3-Bromo-pheny1)-piperidin-1-01-ethanol (Intermediate 45) Br N OH
[0268] 4-(3-Bromo-phenyl)-piperidine (1.2 g, 4.8 mmol) and 2-bromoethanol (0.72 mL, 10 mmol) were diluted with DMF (20 mL) and treated with potassium carbonate (2.7 g, 20 mmol). These were stirred at ambient temperature for 18 then poured onto water and extracted with ethyl acetate. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil (0.6 g, 44%).
EXAMPLE 127. 2-14-(3-{5-Methy1-2-f4-(4-methy1-piperazin-1-y1)-pheny1amino1-PYrimidin-4-y1aminol-phenv1)-niperidin-1-1711-ethano1iCompound LXV(IVI
NH
HO N') -N N
LXXXIV
[02691 A mixture of intermediate 32(0.11 g, 0.38 mmol), intermediate 45 (0.21 g, 0.75 mmol), Pd2(dba)3 (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) was suspended in dioxane (10 mL) and microwaved at 160 C
for 15 min. The reaction mixture was cooled to room temperature and centrifuged down.
The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.075 g, 43%) as a purple solid (0.02 g, 11%).
[02701 IH NMR (500 MHz, DMSO-d6): 5 1.60-1.67 (m, 2H), 1.73 (d, J= 11.3 Hz, 2H), 2.02-2.07 (m, 2H), 2.08 (s, 3H), 2.21 (s, 3H), 2.39-2.45 (m, 7H), 2.95 (d, J=
11.4 Hz, 2H), 3.00 (t, J= 4.66 Hz, 4H), 3.50 (t, J= 6.44 Hz, 2H), 6.76 (d, J= 9 Hz, 2H), 6.92 (d, J 8.5 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.45-7.49 (m, 3.H), 7.66 (d, J= 7.7 Hz, 1H), 7.82 (s, 1H), 8.09 (s, 1H), 8.67 (s, 1H). MS (ES+): nilz 502 (M+H) .
EXAMPLE 128. 443-Bromo-benzenesulfonylamino)-piperidine-1-carboxylic acid tent-butyl ester (Intermediate 46) Br S, [0271] 3-Bromo-benzenesulfonyl chloride (2.2 g, 8.7 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2 g, 10 mmol) were combined and diluted with DCM (50 mL) and TEA (3.6 mL, 26 mmol). After 16 h, reaction was poured into separatory funnel and washed with water. Organic phase was then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil which solidified upon standing (3.6 g, 98%).
EXAMPLE 129. 4-(3-{5-Methy1-244-(4-methyl-piperazin-1-y1)-phenylarninol-pyrimidin-4-y1aminol-benzenesu1fony1amino)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 47) NH, N
NH_ N N
[0272] A mixture of intermediate 32 (0.15 g, 0.518 mmol), intermediate 46 (0.28 g, 0.67 mmol), Pd2(dba)3 (0.024 g, 0.026 mmol), Xantphos (0.03 g, 0.052 mmol) and cesium carbonate (0.34 g, 1 mmol) was suspended in dioxane (10 mL) and microwaved at 160 C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted onto ice. Resulting precipitate dried and carried on directly for deprotection step (0.2 g).
EXAMPLE 130. 345-Methy1-244-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-N-piperidin-4-yl-benzenesulfonamide (Compound LXXXV) H
HNal\L;S\ NH
0/ \O =,cLN N) N N
LXXXV
[0273] Intermediate 47 (0.2 g, 0.32 mmol) was diluted with DCM (10 mL) and treated with TFA (0.3 mL). After 3 h, reaction solvents removed and resulting residue was purified by HPLC (0.01g, 6%).
[0274] 1E1 NMR. (500 MHz, DMSO-d6): 8 1.30-1.35 (m, 2H), 1.56-1.58 (m, 2H), 1.98 (s, 2H), 2.11 (s, 3H), 2.21 (s, 3H), 2.43-2.45 (m, 4H), 2.84-2.87 (m, 2H), 3.02 (t, J= 4.6 Hz, 2H), 6.80 (d, J= 9 Hz, 2H), 7.45-7.51 (m, 4H), 7.78 (br s, 1H), 7.88 (s, 1H), 8.05 (s, 1H), 8.20 (d, J= 7.6 Hz, 1H), 8.53 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 537 (M+H)+.
EXAMPLE 131. N444-(Trifluoromethyl)-3-methylpheny1)-5-methyl-N2-(444-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine hydrochloride (Compound LXXXVI) ,3, NH
I
'f\r N
DOCXVI
[0275] A suspension of intermediate 32 (0.12 g, 0.40 mmol), 1-bromo-3-(trifluoromethyl)-2-methylbenzene (0.14 g, 0.59 mmol), Pd2(dba)3 (37 mg, 0.04 mxnol), Xantphos (47 mg, 0.08 mmol) and cesium carbonate (0.39 g, 1.20 rnmol) in dioxane (20 mL) was degassed with argon for 2 mm then refluxed in a sealed tube for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH3OH/CHC13 as an eluent to afford the title compound as a white solid.
The white was dissolved in CHC13 (30 mL) and titrated with 2 M HC1 in dioxane to pH 1.
The solvent was removed by rotovap and the solid was recrystalized from acetone (25 mg, 13%).
[0276] 1H NMR (500 MHz, DMSO-d6): 62.20 (s, 3H), 2.26 (s, 3H), 2.77 (d, J=
4.5 Hz, 3H), 3.00-3.20 (m, 4H), 3.45 (d, J= 11.6 Hz, 2H), 3.63 (d, J= 12.2 Hz, 2H), 6.71 (d, J= 8.1 Hz, 2H), 7.05 (d, J= 9.0 Hz, 2H), 7.55 (t, J= 7.9 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.77 (d, J
= 7.77 Hz, 1H), 7.94 (s, 1H), 10.13 (s, 1H), 10.60 (s, 1H), 11.28 (s, 1H). MS
(ES+): nilz 457 (M+H)+.
EXAMPLE 132. 5-Methyl-N2,-(4-(4-methylpiperazin-1-y1)pheny1)-/V4-(3-(methylsulfonyl)pheny1)-pyrimidine-2,4-diamine (Compound LXXXVII) NH
N
LXXXVII
[0277] A suspension of intermediate 32 (0.13 g, 0.44 mmol), 1-bromo-3-(methylsulfonyl)benzene (0.24 g, 1.0 mmol), Pd2(dba)3 (40 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mrnol) and cesium carbonate (0.43 g, 1.32 mmol) in dioxane (50 mL) was degassed with argon for 2 min then relaxed for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 30% CH3OH/CHC13 as an eluent to afford the title compound as pale yellow solid (35 mg, 15%).
[0278] 1H NMR (500 MHz, DMSO-d6): 62.11 (s, 3H), 2.23 (s, 3H), 2.46 (hr s, 4H), 3.03 (t, J= 4.4 Hz, 4H), 3.19 (s, 3H), 6.81 (d, J= 9.0 Hz, 2H), 7.45 (d, J= 8.9 Hz, 2H), 7.5-7.6 (m, 2H), 7.91 (s, 1H), 8.05 (s, 1H), 8.36 (d, J= 6.7 Hz, 1H), 8.60 (s, 1H), 8.77 (s, 1H). MS
(ES+): in/z 453 (M+H)+.
EXAMPLE 133. 1-Bromo-3-(propylsulfonvflbenzene (Intermediate 48) Br [0279] To a solution of 3-bromobenzenethiol (0.50 g, 2.6 mmol) in dioxane (50 mL) was added 1-iodopropane (1.1 g, 6.5 mmol) and cesium carbonate (2.2 g, 6.8 mmol) was stirred at reflux until all 3-bromobenzenethiol reacted. The reaction was quenched with saturated NaHCO3 solution (25 mL) and the mixture extracted with CHC13 (60 mL). The product in the CHC13 was refluxed with mCPBA (2.9 g, 13 mmol) until all starting reacted.
The organic layer was washed with 2M NaOH to remove the excess of mCPBA, dried over Na2SO4 and filtered. The filtrate was concentrated and the crude product was purified with silica gel column with 1:1 hexanes/CHC13 as an eluent to yield colorless oil (0.30 g, 43%
in 2-steps).
[0280] 1HNMR (500 MHz, DMSO-d6): 0.92 (t, J= 7.4 Hz, 3H), 1.52-1.60 (m, 2H), 3.35-3.38 (m, 2H), 7.63 (t, J= 8.0 Hz, 1H), 7.88-7.91 (m, 1H), 7.95-7.98 (m, 1H), 8.04 (t, J 1.8 Hz, 1H).
EXAMPLE 134. 5-Methyl-N244-(4-methylpiperazin-1-yl)pheny1)-/V4-(3-(propylsulfonyl)pheny1)-pyrimidine-2,4-diamine hydrochloride (Compound LXXXVIH) N
NH
0 N õ1 N
LXXXVIII
[0281] A suspension of intermediate 32 (0.25 g, 0.84 mmol), intermediate 48 (0.26 g, 1 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), Xantphos (16 mg, 0.03 mmol) and cesium carbonate (0.82 g, 2.52 mmol) in dioxane (50 mL) was degassed with argon for 2 mm then refluxed for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH3OH/CHC13 as an eluent to afford the title compound as a white solid. The white was dissolved in CHC13 (30 mL) and titrated with 2 M HC1 in dioxane to pH 1. The solvent was removed by rotovap and the solid was recrystalized from methanol (65 mg, 15%).
[0282] NMR (500 MHz, DMSO-d6): 0.90 (t, J= 7.4 Hz, 3H), 1.50-1.60(m, 2H),2.18 (s, 3H), 2.81 (s, 3H), 3.00-3.13 (m, 4H), 3.27 (t, J= 7.7 Hz, 2H), 3.48 (d, J=
10.9 Hz, 2H), 3.75 (d, J= 11.4 Hz, 2H), 6.95 (d, J= 8.8 Hz, 2H), 7.27 (d, J= 8.9 Hz, 2H), 7.64 (t, J= 8.0 Hz, 1H), 7.73 (d, J= 7.8 Hz, 1H), 7.93 (s, 1H), 8.00 (s, 1H), 8.07 (s, 1H), 9.92 (s, 1H), 10.36 (s, 1H), 10.99 (s, 1H). MS (ES+): nilz 481 (M+H)+.
EXAMPLE 135. 3-(Morpholinomethyl)benzenamine (Intermediate 49) [0283] Zinc chloride (0.1 g, 0.73 mmol) was added to the solution of 3-nitrobenzaldehyde ( 5.9 g, 39.02 mmol), morpholine (3.4 g, 39.02 mmol), sodium cyanoborohydride (2.7 g, 43 mmol) in methanol (50 mL) at room temperature. The solution was heated to reflux for 1 hour. After cooling down , the reaction was quenched by water ( 2 mL) and the methanol was removed by rotovap. The crude product was dissolved in 2M NaOH (50 mL) and extracted by CHC13, dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum.
[0284] The above crude product in methanol (200mL) was reduced by Raney Ni and hydrazine at room temperature. The reaction was monitored by TLC in ethyl acetate. After all starting material reacted, the methanol was removed by rotovap. The crude was purified by silica gel with ethyl acetate as an eluent to yield a white solid (1.5 g, 50% in 2-steps).
[0285] 1H NMR (500 MHz, DMSO-d6): 2.31 (s, 4H), 3.28 (s, 2H), 3.56 (t, J=
4.6 Hz, 4H), 4.97 (s, 2H), 6.40-6.45 (m, 2H), 6.53 (t, J= 1.8 Hz, 1H), 6.93 (t, J= 7.7 Hz, 1H).
EXAMPLE 136 5-Methyl-N2-(3-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Intermediate 50) N
N)N N) [0286] A mixture of 2-chloro-5-methylpyrimidin-4-amine (0.17 g, 1.17 mmol) and interrnediate 49 (0.25 g, 1.30 mmol) was suspended in acetic acid (10 mL) and heated at 100 C for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-8.
The resulting solution was extracted with CHC13 (100 mL) and the organic layer separated.
The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by silica gel column with 10 %
CH3OH/Et0Ac as an eluent to afford the title compound as oil (0.15g, 43%).
[0287] 1H NMR (500 MHz, DMSO-d6): 1.91 (s, 3H), 2.35 (s, 4H); 3.17 (s, 2H), 3.57(t, J
= 4.4 Hz, 4H), 6.37 (s, 2H), 6.78 (d, J= 7.5 Hz, 1H), 7.13 (t, J= 7.8 Hz, 1H), 7.59 (s, 1H), 7.69 (s, 1H), 7.74 (d, J= 9.3 Hz, 1H), 8.68 (s, 1H).
EXAMPLE 137. N-tert-Buty1-3-15-methy1-243-morpho1in-4-ylmethy1-pheny1amino)-pyrimidin-4-ylaminol-benzenesulfonamide hydrochloride (Compound LVOCIX) HO
NH
6 N r0 N N
LVOCIX
[0288] A suspension of intermediate 50 (1.0 g, 3.42 minol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.28 g, 4.28 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), Xantphos (40 mg, 0.07 mmol) and cesium carbonate (3.34 g, 10.24 mmol) in dioxane (50 mL) was degassed with argon for 2 min then refluxed for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH3OH/CHC13 as an eluent to afford the title compound as a white solid.
The white was dissolved in hot dioxane (150 mL) and titrated with 2 M HC1 in dioxane to pH
1. The solvent was removed by rotovap and the solid was recrystalized from methanol (0.15 g, 8%).
102891 1H NMR (500 MHz, DMSO-d6): 1.08 (s, 9H), 2.20 (s, 3H), 3.0-3.2 (in, 4H), 3.7-4.0 (m, 4H), 4.23 (s, 2H), 7.33 (t, J-= 7.9 Hz, 1H), 7.38 (d, J= 7.7 Hz, 1H), 7.48 (s, 1H), 7.55-7.65 (m, 3H), 7.71 (d, J= 7.9 Hz, 1H), 7.90 (d, J= 7.4 Hz, 1H), 8.01 (s, 1H), 9.96 (br s, 1H), 10.61 (br s, 1H), 11.31 (br s, 1H). MS (ES+): inlz 511 (M+H)+.
EXAMPLE 138. 2-Chloro-5-methyl-N-(3,5-dimethvlphenyl)pyrimidin-4-amine (Intermediate 51) NH
N
I
CI
[0290] A mixture of 1-bromo-3,5-dimethylbenzene (104 [IL, 0.77 mmol), 2-chloro-methyl-pyrimidin-4-ylamine (104 mg, 0.72 mmol), Pd(OAC)2 (15 mg, 0.07 mmol), Xantphos (83 mg, 0.14 mmol) and potassium tert-butoxide (159 mg, 1.42 mmol) in dioxane (8 mL) was microwaved at 160 C for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow oil (89 mg, 50%). MS (ES+): nez 248 (M+H)+.
EXAMPLE 139. 5-Methyl-/V4-(3.5-dimethylpheny1)-N2-(4-(piperidin-4-vloxy)phenyllpyrimidine-2,4-diamine (Compound XC1 N 0, NH
j.N)N
XC
[0291] A mixture of intermediate 51 (89 mg, 0.36 mmol), and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (139 mg, 0.47 mmol) in acetic acid was stirred at room temperature for 16h, then heated to 95 C for 2 h. The reaction mixture was concentrated in vacuo, and purified by preparative HPLC. The product was basified with NaHCO3 (aq)(10 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated. The freebase was taken up in Me0H (5 mL) and conc HC1 (5 drops) and after 2 mm was concentrated in vacuo in the presence of DCM and hexanes to afford the HC1 salt of the title compound as an off-white solid (63 mg, 40%).
[0292] 111 NMR (500 MHz, DMSO-d6): 8 1.72-1.83.(m, 2H), 2.02-2.08 (m, 211), 2.14_(d, J
= 0.6 Hz, 311), 2.24 (s, 6H), 3.04-3.15 (m, 2H), 3.21-3.31 (m, 211), 4.57-4.60 (m, 1H), 6.85 (s, 111), 6.91 (d, J= 8.9 Hz, 211), 7.20 (s, 211), 7.37 (d, J= 8.9 Hz, 211), 7.85 (s, 1H), 8.50 (br s, 1H), 8.56 (br s, 1H), 9.36 (br s, 1H), 10.10 (br s, 1H). MS (ES+): ni/z 404 (M+H)+.
EXAMPLE 140. 2-Chloro-N-(3,5-dimethoxypheny1)-5-methylpyrimidin-4-amine (Intermediate 52) O NH
I
CI
[0293] A mixture of 1-bromo-3,5-dimethoxybenzene (436 mg, 2.01 mmol), 2-chloro-methyl-pyrimidin-4-ylamine (287 mg, 2.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), Xantphos (237 mg, 0.41 mmol) and potassium tert-butoxide (448 mg, 3.99 mmol) in dioxane (15 mL) and DMF (5 mL) was microwaved at 160 C for 20 mm. The reaction mixture was cooled to room temperature and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow solid (182 mg, 33%).
[0294] NMR
(500 MHz, DMSO-d6): 6 2.17 (s, 3H), 3.74 (s, 6H), 6.27 (t, J= 2.2 Hz, 1H), 6.99 (d, i=2.2 Hz, 2H), 8.06 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 280 (M+H)+.
EXAMPLE 141. /V4-(3,5-Dimethoxypheny1)-5-methy1-N244-(piperidin-4-yloxy)phenybpyrimidine-2,4-diainine (Compound XCI) NH
N
I
N NH
XCI
[0295] A mixture of intermediate 52 (100 mg, 0.36 mmol), and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.36 mmol) in acetic acid was heated to 95 C for 2 h. The reaction mixture was concentrated in vacuo, and purified by preparative HPLC to afford the TFA salt of the title compound as a tan solid (75 mg, 39%).
[0296] NMR
(500 MHz, DMSO-d6): 5 1.74-1.83 (in, 2H), 2.03-2.11 (in, 2H), 2.15 (s, 3H), 3.06-3.15 (in, 2H), 3.21-3.30 (m, 2H), 3.69 (s, 6H), 4.57-4.60 (m, 1H), 6.39 (t, J- 2.2 Hz, 1H), 6.80 (d, J=2.2 Hz, 2H), 6.89 (d, J= 8.9 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.86 (s, 1H), 8.53 (br s, 1H), 8.58 (br s, 1H), 9.49 (br s, 1H), 10.24 (br s, 1H). MS
(ES+): in/z 436 (M+H)+.
EXAMPLE 142. 5-Methyl-N2-(4-(4-methylpiperazin-1-yl)pheny1)-/V4-(3-(piperidin-yl)phenybpyrimidine-2,4-diamine (Compound XCII), N el NH
I
N
XCII
[0297] A mixture of 1-(3-bromophenyl)piperidine (91 mg, 0.38 mmol), intermediate 32 (99 mg, 0.33 mmol), Pd2(dba)3 (15 mg, 0.02 mmol), Xantphos (24 mg, 0.04 mmol) and cesium carbonate (219 mg, 0.67 mmol) in dioxane (4 mL) was microwaved at 160 C for 15 min. The reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in methanol, and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified by preparative HPLC to afford the TFA salt of the title compound as an off-white solid (14 mg, 8%).
[0298] 11-1NMR (500 MHz, DMSO-d6): 5 1.47-1.53 (m, 2H), 1.56-1.61 (m, 4H), 2.07 (s, 3H), 2.21 (s, 3H), 2.44 (t, J=4.9 Hz, 4H), 3.01 (t, J-4.9 Hz, 4H), 3.08 (t, J5.4 Hz, 4H), 6.63 (dd, J = 8.2, 2.3 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H), 7.12 (t, J= 8.3 Hz, 1H), 7.14 (s, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.81 (s, 1H), 8.00 (s, 1H), 8.67 (s, 1H). MS
(ES+): ni/z 458 (M+H)+.
EXAMPLE 143. N4-(341H-Pyrrol-1-y1)pheny1)-5-methyl-N2-(4-(4-methylpiperazin-1-ybphenyl)pyrimidine-2,4-diamine (Compound XCIII) el el NH N-- N N) N
[0299] A mixture of 1-(3-bromopheny1)-1H-pynole (86 mg, 0.39 mmol), intermediate 32 (99 mg, 0.33 mmol), Pd2(dba)3 (16 mg, 0.02 mmol), Xantphos (26 mg, 0.05 mmol) and cesium carbonate (215 mg, 0.66 nunol) in dioxane (4 mL) was microwaved at 160 C for 15 mm. The reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in methanol, and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified by preparative HPLC to afford the TFA salt of the title compound as an off-white solid (32 mg, 18%).
[0300] 1H NMR (500 MHz, DMSO-d6): 8 2.11 (s, 3H), 2.21 (s, 3H), 2.42 (t, J=4.9 Hz, 4H), 2.95 (t, J=4.9 Hz, 4H), 6.24 (t, J=2.2 Hz, 2H), 6.58 (d, J=8.9 Hz, 2H), 7.23 (dd, J-7 .8, 1.8 Hz, 1H), 7.31 (t, J= 2.2 Hz, 2H), 7.37 (t, J=8.1 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.86 (t, J=2.2 Hz, 1H), 7.87 (s, 1H), 8.30 (s, 1H), 8.74 (s, 1H). MS
(ES+): m/z 440 (M+H)+.
EXAMPLE 144. 5-1244-(1-tert-Butoxycarbonyl-piperidin-4-yloxy)-phenylaminol-5-methyl-pyrimidin-4-ylaminol-indole-1-carboxylic acid tert-butyl ester (Intermediate 53) NyO
N
NH
N
[0301] A mixture of tert-butyl 5-bromo-1H-indole-1-carboxylate (161 mg, 0.54 mmol), intermediate 42 (202 mg, 0.50 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), Xantphos (36 mg, 0.07 mmol) and cesium carbonate (321 mg, 0.98 mmol) in dioxane (5 mL) was microwaved at 160 C for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM. The filtrate was concentrated and purified by gradient flash chromatography (0-20% Me0H in DCM) to afford the title compound as a light-brown solid (290 mg, 94%).
MS (ES+): nilz 615 (M+H)+.
=
EXAMPLE 145. N4-(1H-Indol-5-y1)-5-methyl-N2-0-(Piperidin-4-vioxy)phenyi)pyrimidine-214-diamine (Compound XCI'V) NH
NN NH
40) XCIV
[03021 To a solution of acetyl chloride (670 pL, 9.42 mmol) in methanol (22 mL) was added intermediate 53 (290 mg, 0.47 mmol), and the reaction mixture was heated to 60 C for 4 h. The mixture was concentrated in vacuo and purified by preparative HPLC to afford the TFA salt of the title compound as a brown solid (6 mg, 2%).
[03031 1H NMR (500 MHz, DMSO-d6): 8 1.70-1.78 (m, 2H), 1.98-2.07 (m, 2H), 2.16 (s, 3H), 3.02-3.11 (m, 2H), 3.21-3.30 (m, 2H), 4.44-4.53 (m, 1H), 6.43 (s, 1H), 6.75 (d, J= 8.2 Hz, 2H), 7.16 (d, J= 8.4 Hz, 1H), 7.31 (d, J 8.7 Hz, 2H), 7.40-7.42 (m, 2H), 7.71 (s, 1H), 7.78 (s, 1H), 8.48 (br s, 1H), 8.54 (br s, 1H), 9.65 (br s, 1H), 9.99 (br s, 1H), 11.18 (s, 1H).
MS (ES+): nilz 415 (M+H)+.
EXAMPLE 146. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(6-piperazin-1-171-pyridin-3-14)-pyrimidine-2,4-diamine (Compound XCV) CI
N
NNN
XCV
[03041 A mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(5-amino-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester (0.10 g, 0.36 mmol), Pd2(dba)3 (30 mg, 0.033 Xantphos (35 mg, 0.06 nunol) and cesium carbonate (0.23 g, 0.71 mmol) in dioxane/DMF (3/1, 4 triL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 30 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to Et0Ac) to afford the Boc-protected precursor. To a solution of the precursor in DCM (5 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 30 min, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid triturated in a mixture of hexanes/Et0Ac (10/1, 55 mL). After filtration, the title compound was obtained as a white solid (20 mg, 13%).
[0305] 1H NMR (500 MHz, DMSO-d6): 6 2.09 (s, 3H), 2.81 (t, J= 5.0 Hz, 4H), 3.29-3.31 (m, 4H), 3.73 (s, 3H), 6.70 (d, J= 9.1 Hz, 1H), 7.26 (d, J= 8.6 Hz, 1H), 7.42 (d, J= 9.1 Hz, 1H), 7.49 (d, J= 2.2 Hz, 1H), 7.76 (dd, .1= 9.1, 2.6 Hz, 1H), 7.86 (s, 1H), 8.29 (s, 1H), 8.31 (d, J¨ 2.6 Hz, 1H), 8.71 (s, 1H). MS (ES+): ni/z 426 (M+H)+.
EXAMPLE 147. 4-(4-Amino-2-methoxycarbonvi-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 54) NBoc [0306] To a solution of 4-(2-methoxycarbony1-4-nitro-pheny1)-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol) in Me0H (30 mL) was added 10 wt% Pd/C
(0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 2 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo.
The crude amino-compound was used in the next step without purification. MS (ES+): tn/z (M+H)+, EXAMPLE 148. 544-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylamino1-2-piperazin4-yl-benzoie acid methyl ester (Compound XCVI1 CI
NH 0 r.NH
NN
I
XCVI
[0307] A mixture of intermediate 31 (0.10 g, 0.35 mmol), intermediate 54 (0.14 g, 0.42 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) was suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 2.5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60% Et0Ac/hexanes) to afford the Boc-protected precursor. To a solution of the precursor in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and = filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 24%).
[0308] 1H NMR (500 MHz, DMSO-d6): 32.11 (s, 3H), 2.80-2.90 (m, 8H), 3.73 (s, 3H), 3.74 (s, 3H), 6.98 (d, J= 8.9 Hz, 1H), 7.25 (d, J= 8.5 Hz, 1H), 7.40-7.48 (in, 2H), 7.69 (dd, J
---- 8.9, 2.6 Hz, 1H), 7.90 (d, J= 2.6 Hz, 1H), 7.91 (s, 1H), 8.36 (s, 1H), 9.04 (s, 1H). MS
(ES+): m/z 483 (M+H)+.
EXAMPLE 149. 5-Amino-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (Intermediate 55) 0,,No =
[0309] A suspension of 5-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6.0 mmol), 1-(2-chloro-ethyl)-pynolidine hydrochloride (1.2 g, 7.1 mmol) and cesium carbonate (5.0 g, 15 mmol) in DMF (40 mL) was heated at 60 C for 17 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with Et0Ac (2 x 50 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% Me0H/DCM) to afford the title compound (0.2 g, 13%) as a light brown solid.
MS (ES+): m/z 265 (M+H)+.
EXAMPLE 150. 5-[4-(Benzo[(31dioxo1-4-ylamino)-5-methyl-pyrimidin-2-ylamino1-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (Compound XCVII) NH
\/L
N NO
-N N
XCVII
[0310] A mixture of intermediate 30 (0.15 g, 0.57 mmol), intermediate 55 (0.20 g, 0.75 mmol), Pd2(dba)3 (50 mg, 0.055 mmol), Xantphos (60 mg, 0.10 mmol) and cesium carbonate (0.30 g, 0.92 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (30 mg, 11%).
[0311] 1H NMR (500 MHz, DMSO-d6): 5 1.65-1.72 (m, 4H), 2.07 (s, 3H), 2.50-2.62 (m, 4H), 2.75-2.85 (m, 2H), 3.73 (s, 3H), 4.02 (t, J 5.8 Hz, 2H), 5.88 (s, 2H), 6.78-6.88 (m, 3H), 6.92 (dd, J= 8.0, 2.1 Hz, 1H), 7.75-7.80 (m, 2H), 7.83 (s, 1H), 8.22 (s, 1H), 8.89 (s, 1H). MS (ES+): in/z 492 (M+H)+.
EXAMPLE 151. N-tert-Buty1-3-{5-methy1-2-14-(piperidin-4-yloxy)-phenylaminol-pyrimidin-4-ylamino}-benzenesulfonamide (Compound XCVIII) A Si NH
=i \ =
NN NH
XCVIII
[0312] A mixture of intermediate 33 (0.15 g, 0.42 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.51 rrunol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C
for 20 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the pH adjusted with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by HPLC. The corrected fractions were combined, poured into saturated NaHCO3 solution (30 mL) and extracted with Et0Ac (2 x 30 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (20 mg, 9%).
[0313] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 1.65-1.73 (m, 2H), 1.95-2.05 (m, 2H), 2.12 (s, 3H), 2.89-2.95 (m, 2H), 3.10-3.20 (m, 2H), 4.40 /1.45 (m, 1H), 6.84 (d, .1= 9.1 Hz, 2H), 7.45-7.60 (m, 6H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.55 (s, 1H), 8.81 (s, 1H). MS
(ES+): m/z 511 (M+H) .
EXAMPLE 152. 2-(5-Amino-pyridin-2-yloxy)-ethanol (Intermediate 56) OH
[0314] To a solution of 2-(5-nitro-pyridin-2-yloxy)-ethanol (1.0 g, 5.4 mmol) in Me0H
(30 mL) was added 10 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 1 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS (ES+): in/z 155 (M+H)+.
EXAMPLE 153. 2-{5-[4-(Senzo[1,3]dioxol-4-ylarnino)-5-methyl-pyrimidin-2-ylamino]-pyridin-2-yloxyl-ethanol (Compound XCIX) NH
r()OH
NNN
XCIX
[0315] A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 56 (0.10 g, 0.65 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.26 g, 0.80 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (50 mg, 35%).
[0316] 1H NMR (500 MHz, DMSO-do): 5 2.06 (s, 3H), 3.66 (q, J= 5.4 Hz, 2H), 4.15 (t, J
= 5.2 Hz, 2H), 4.77 (t, J= 5.5 Hz, 2H), 5.91 (s, 2H), 6.52 (d, J = 9.0 Hz, 1H), 6.78-6.90 (m, 3H), 7.82 (s, 1H), 7.96 (dd, J= 8.9, 2.7 Hz, 1H), 8.22 (d, J= 2.6 Hz, 1H), 8.27 (s, 1H), 8.84 (s, 1H). MS (ES+): m/z 382 (M+H)+.
EXAMPLE 154. 142-(2-Methoxy-4-nitro-phenoxy)-ethyThpyrrolidine (Intermediate [0317] A suspension of potassium 2-methoxy-4-nitro-phenolate (2.0 g, 9.7 mmol), 142-chloro-ethyp-pyrrolidine hydrochloride (2.0 g, 12 mmol) and cesium carbonate (7.0, 22 mmol) in DMF (35 mL) was heated at 80 C for 16 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with Et0Ac (2 x 50 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and used in the next step without purification.
MS (ES+): m/z 267 (M+H)+. =
EXAMPLE 155. 3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (Intermediate [03181 To a solution of intermediate 57 (1.7 g, 6.4 nunol) in Me0H (30 mL) was added 10 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 1 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS
(ES+): m/z 237 (M+H)+.
EXAMPLE 156. N4-Benzo[1,31dioxo1-4-yl-N2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-pheny11-5-methyl-pyrimidine-2,4-diamine (Compound C) N
[03191 A mixture of intermediate 30 (0.10 g, 0.38 mmol), interniediate 58 (0.11 g, 0.46 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (50 mg, 28%).
[0320] 1H NMR (500 MHz, DMSO-d6): 5 1.65-1.72 (in, 4H), 2.06 (s, 3H), 2.50-2.62 (m, 4H), 2.75-2.85 (m, 2H), 3.50 (s, 3H), 3.94 (t, J= 6.1 Hz, 2H), 5.84 (s, 2H), 6.67 (d, J= 8.8 Hz, 1H), 6.78 (dd, J= 7.8, 1.1 Hz, 1H), 6.83 (t, J= 7.9 Hz, 1H), 6.92 (dd, J=
8.1, 1.1 Hz, 1H), 7.14 (dd, J= 8.7, 2.4 Hz, 1H), 7.23(d, I-- 2.4 Hz, 1H), 7.83 (s, 1H), 8.21 (s, 1H), 8.69 (s, 1H). MS (ES+): m/z 464 (M+H)+.
EXAMPLE 157. N-tert-Buty1-342-(4-imidazol-1-yl-phenylamino)-5-methyl-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CI) /S\ NH
0"0 N/>
t 40 N N
CI
[0321] A mixture of intermediate 33 (0.40 g, 1.1 mmol), 4-imidazol-1-yl-phenylamine (0.20 g, 1.3 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (0.80 g, 2.5 mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 30 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (40 mL). The combined aqueous layers were extracted with Et0Ac (2 x 40 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.15 g, 28%).
[0322] 1H NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.15 (s, 3H), 7.07 (s, 1H), 7.43 (d, J¨ 9.0 Hz, 2H), 7.50-7.60 (m, 3H), 7.61 (s, 1H), 7.79 (d, J = 9.0 Hz, 2H), 7.98 (s, 1H), 8.08-8.13 (m, 3H), 8.64 (s, 1H), 9.19 (s, 1H). MS (ES+): m/z 478 (M+H)+.
EXAMPLE 158. N-tert-Buty1-3-f2-(4-imidazo1-1-y1methyl-pheny1amino)-5-methy1-pyrimidin-4-ylamino]-benzenesulfonamide (Compound CII) NH
NH
0"0 NI
I
N
CII
[0323] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-imidazol-1-ylmethyl-phenylamine (60 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The -filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 29%).
[0324] NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.13 (s, 3H), 5.07 (s, 2H), 6.89 (s, 1H), 7.12 (d, J= 8.6 Hz, 2H), 7.15 (s, 1H), 7.46 (t, J= 7.9 Hz, 1H), 7.49-7.52 (m, 1H), 7.56 (s, 1H), 7.63 (d, J= 8.6 Hz, 2H), 7.72 (s, 1H), 7.94 (s, 1H), 8.09 (s, 1H), 8.14 (d, J= 8.1 Hz, 1H), 8.60 (s, 1H), 9.02 (s, 1H). MS (ES+): m/z 492 (M+H)+.
EXAMPLE 159. 2-(4-Amino-phenoxy)-ethanol (Intermediate 59) [0325] A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in Me0H
(30 mL) was flushed with argon and then charged with 10 wt% Pd/C (0.1 equiv by wt). The mixture was evacuated under house vacuum and then refilled with hydrogen from hydrogen balloon. The cycle was repeated again and the mixture stirred at room temperature for 2 h.
The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo to furnish the title compound (1.8 g, 99%) as a brown solid. MS
(ES+): in/z 154 (M+H)+.
EXAMPLE 160. N-tert-Buty1-3-{244-(2-hydroxy-ethoxy)-pheny1amino1-5-methy1-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CIII) NH
O"O
OH
N N
CIII
[0326] A mixture of intermediate 33 (0.10 g, 0.28 nu-nol), intermediate 59 (55 mg, 0.36 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).
[0327] 1HNMR (500 MHz, DMSO-d6): 5 1.12 (s, 9H), 2.12 (s, 3H), 3.69 (q, J =
5.2 Hz, 2H), 3.91 (t, J = 5.1 Hz, 2H), 4.82 (t, J= 5.5 Hz, 2H), 6.80 (d, J= 9.1 Hz, 2H), 7.45-7.50 (m, 2H), 7.52 (d, J=-= 9.0 Hz, 2H), 7.55 (s, 1H), 7.90 (s, IH), 8.08-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): Tn/z 472 (M+H)+.
EXAMPLE 161. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N244-piperazin-1-ylmethyl-pheny1)-pyrimidine-2,4-diarnine (Compound CIV), CI
NH
N4 Nr.'" 10 NN (=õ,õNH
CIV
[0328] A
mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(4-amino-benzy1)-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in dioxane/DMF
(3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60%
Et0Ac/hexanes) to afford the Boc-protected precursor. To a solution of the precursor in DCM
(5 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 1 h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (13 mg, 9%).
[0329] NMR
(500 MHz, DMSO-d6): 8 2.11 (s, 3H), 2.30-2.40 (m, 4H), 2.83 (t, J= 4.8 Hz, 4H), 3.37 (s, 2H), 3.75 (s, 3H), 7.08 (d, J= 8.6 Hz, 2H), 7.29 (d, J= 8.6 Hz, 1H), 7.43 (dd, J= 8.6, 2.2 Hz, 1H), 7.47 (d, J= 2.2 Hz, 1H), 7.59 (d, J= 8.6 Hz, 2H), 7.91 (s, 1H), 8.37 (s, 1H), 8.99 (s, 1H). MS (ES+): nilz 439 (M+H)+.
EXAMPLE 162. N-tert-Buty1-3-{5-methyl-2-1.4(2-methy1-imidazo1-1-y1)-pheny1amino1-pyrimidin-4-y1aminol-benzenesu1fonamide (Compound CV).
H
>,N,/s\
NH
µ0 N
CV
[03301 A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(2-methyl-imidazol-1-y1)-phenylamine (60 mg, 0.35 nunol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (30 mg, 22%).
[03311 1H NMR (500 MHz, DMSO-d6): 8 1.11 (s, 9H), 2.15 (s, 3H), 2.24 (s, 3H), 6.87 (d, J= 1.2 Hz, 1H), 7.18 (d, J= 1.3 Hz, 1H), 7.22 (d, 8.9 Hz, 2H), 7.50-7.55 (m, 2H), 7.56 (s, 1H), 7.79 (d, 8.9 Hz, 2H), 7.98 (s, 1H), 8.07-8.10 (m, 2H), 8.65 (s, 1H), 9.26 (s, 1H).
MS (ES-0: m/z 492 (M+H)+.
EXAMPLE 163. N-tert-Buty1-3-{5-methy1-2-[442-methyl-imidazol-1-ylmethyl)-phenv1amino]-pyrimidin-4-y1aminol-benzenesu1fonamide (Compound CVI) H
NH
Ngki CVI
[0332] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(2-methyl-imidazol-1-ylmethyl)-phenylamine (65 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (30 mg, 21%).
[0333] 1H NMR (500 MHz, DMSO-d6): 1.12 (s, 9H), 2.13 (s, 3H),2.24 (s, 3H), 5.01 (s, 2H), 6.73 (d, J= 1.2 Hz, 1H), 7.01 (d, J= 8.6 Hz, 2H), 7.07 (d, J= 1.1 Hz, 1H), 7.44 (t, J=
7.9 Hz, 1H), 7.48-7.51 (m, 1H), 7.56 (s, 1H), 7.62 (d, J= 8.6 Hz, 2H), 7.94 (s, 1H), 8.08 (s, 1H), 8.12 (d, J= 8.1 Hz, 1H), 8.60 (s, 1H), 9.02 (s, 1H). MS (ES+): m/z 506 (M+H)4r.
EXAMPLE 164. N-tert-Buty1-3-1-5-methy1-244-pyridin-4-ylmethyl-phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CVII) /Sµ\ NH
t I N
N N
CVII
[0334] A mixture of inteunediate 33 (0.10 g, 0.28 mmol), 4-Pyridin-4-ylmethyl-phenylamine (65 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (45 mg, 32%).
[0335] 11-1NMR (500 MHz, DMSO-d6): 8 1.11 (s, 9H), 2.13 (s, 3H), 3.87 (s, 2H), 7.07 (d, J= 8.6 Hz, 2H), 7.22 (d, J= 6.0 Hz, 2H), 7.43 (t, J= 7.9 Hz, 1H), 7.47-7.50 (m, 1H), 7.56 (d, J= 6.3 Hz, 2H), 7.58 (s, 1H), 7.93 (s, 1H), 8.09 (s, 1H), 8.13 (d, J= 8.0 Hz, 1H), 8.44 (d, J= 5.8 Hz, 2H), 8.58 (s, 1H), 8.94 (s, 1H). MS (ES+): ni/z 503 (M+H)+.
EXAMPLE 165. N-tert-Buty1-345-methyl-244-morpholin-4-yl-phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CVIII) >N1-1,./s\
NH ro 0-0 ),õ
=
CVIII
[0336] A mixture of intetinediate 33 (0.10 g, 0.28 mmol), 4-morpholin-4-yl-phenylamine (60 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a grey solid (45 mg, 32%).
[0337] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.12 (s, 3H), 3.00 (t, J=
4.8 Hz, 4H), 3.73 (t, J= 4.8 Hz, 4H), 6.82 (d, Jr 9.1 Hz, 2H), 7.45-7.52 (m, 4H), 7.56 (s, 1H), 7.89 (s, 1H), 8.10-8.17 (m, 2H), 8.52 (s, 1H), 8.73 (s, 1H). MS (ES+): nilz 497 (M+H) .
EXAMPLE 166. N-tert-Buty1-3-[5-methy1-2-(441,2,41triazol-1-ylmethyl-phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CIX) H
>,N NH
,./" s\
N N-N N
CIX
=
[0338] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-[1,2,4]triazo1-1-y1methyl-phenylamine (60 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 rnmol), Xantphos (30 mg, 0.052 mm.ol) and cesium carbonate (0.20 g, 0.61 rnmol)in dioxane (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (37 mg, 27%).
[0339] 11-1 NMR (500 MHz, DMSO-d6): 8 1.17 (s, 9H), 2.13 (s, 3H), 5.29 (s, 2H), 7.14 (d, J= 8.6 Hz, 2H), 7.46 (t, J 7.8 Hz, 1H), 7.48-7.51 (m, 1H), 7.56 (s, 1H), 7.63 (d, 8.6 Hz, 2H), 7.94 (s, 1H), 7.95 (s, 1H), 8.08 (s, 1H), 8.13 (d, J= 8.0 Hz, 1H), 8.59 (s, 1H), 8.60 (s, 1H), 9.04 (s, 1H). MS (ES+): nilz 493 (M+H)+.
EXAMPLE 167. N-tert-Buty1-3-{5-methyl-2-[4-(4-methyl-imidazol-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CX) H
NH ,-N
\O NN
CX
[0340] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-methy1-imidazol-1-y1)-phenylamine (60 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac'(2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (20 mg, 15%).
[03411 1H NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.15 (s, 3H), 2.16 (s, 3H), 7.30 (s, 1H), 7.38 (d, J= 9.0 Hz, 2H), 7.50-7.56 (m, 2H), 7.57 (s, 1H), 7.76 (d, J¨ 9.0 Hz, 2H), 7.96 (s, 1H), 7.97 (s, 1H), 8.09-8.13 (m, 2H), 8.63 (s, 1H), 9.16 (s, 1H). MS
(ES+): in/z 492 (M+H)4- .
EXAMPLE 168. N-tert-Butyl-3-[5-methyl-2-(4-[1,2,4]triazol-1-yl-phenvlamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXI) H
NH N=--\
0/ 0N,N
N
CXI
[0342] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 441,2,4]triazol-1-yl-phenylamine (55 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 ni.M.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na?Sat and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 29%).
[0343] 1H NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.15 (s, 3H), 7.50-7.58 (m, 3H), 7.63 (d, J= 9.1 Hz, 2H), 7.83 (d, J= 9.0 Hz, 2H), 7.99 (s, 1H), 8.09 (s, 1H), 8.10-8.15 (m, 1H), 8.17 (s, 1H), 8.66 (s, 1H), 9.12 (s, 1H), 9.27 (s, 1H). MS (ES+): m/z 479 (M+H)+.
EXAMPLE 169. N-tert-Butv1-3-{5-methyl-2-[341H-tetrazol-5-y1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXII) N,F1 NH
HN-N
CXII
[0344] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 3-(1H-tetrazol-5-y1)-phenylamine (55 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 nunol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 nit) was sealed in a microwave reaction tube and irradiated with microwave at 160 C. for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).
[0345] 1H NMR (500 MHz, DMSO-d6): 61.13 (s, 9H), 2.15 (s, 3H), 7.26 (t, J=
7.9 Hz, 1H), 7.38 (t, J= 8.0 Hz, 1H), 7.44 (dd, J= 7.9, 1.1 Hz, 1H), 7.50 (d, J= 7.6 Hz, 1H), 7.58 (s, 1H), 7.79 (dd, J= 8.1, 1.4 Hz, 1H), 7.98 (s, 1H), 8.16 (s, 1H), 8.22 (s, 1H), 8.27 (d, J= 7.8 Hz, 1H), 8.57 (s, 1H), 9.08 (s, 1H). MS (ES+): m/z 480 (M+H)+
EXAMPLE 170. 4(1H-Tetrazol-5-y1)-phenylamine (Intermediate 60) HN
[0346] To a solution of 5-(4-nitro-phenyl)-1H-tetrazole (1.0 g, 5.2 mmol) in Me0H (30 mL) was added 10 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated, refilled with hydrogen (3 cycles) and stirred at room temperature for 1.5 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS (ES+): nilz 162 (M+H)+.
EXAMPLE 171. N-tert-Buty1-3-{5-methyl-2-14-(1H-tetrazol-5-y1)-phenylarninol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXIII) H
NH HN-1\,1, \O ,N
N 401 .1\1 CXIII
[0347] A mixture-of intennediate 33 (0.10 g, 0.28 mmol), intermediate 60 (60 mg, 0.37 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1; 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).
[0348] 1H NMR (500 MHz, DMSO-d6): 5 1.13 (s, 9H), 2.16 (s, 3H), 7.52-7.56 (rn, 2H), 7.57 (s, 1H), 7.83 (s, 4H), 8.01 (s, 1H), 8.08 (s, 1H), 8.13-8.19 (m, 1H), 8.69 (s, 1H), 9.34 (s, 1H). MS (ES+): nz/z 480 (M+H)+ .
EXAMPLE 172. 3-1244-(4-Acetyl-piperazin-1-y1)-phenylaminol-5-methyl-pyrimidin-ylaminol-N-tert-butyl-benzenesulfonamide (Compound CXIV) // 1S\
N H N
\O
N
I
N
CXIV
[0349] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 144-(4-amino-phenyl)-piperazin-1-yll-ethanone (80 mg, 0.36 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (55 mg, 37%).
[0350] 1H NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.04 (s, 3H), 2.12 (s, 3H), 2.97 (t, 5.2 Hz, 2H), 3.03 (t, J= 5.1 Hz, 2H), 3.57 (q, J---= 5.4 Hz, 4H), 6.85 (d, J=
9.0 Hz, 2H), 7.46-7.52 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.17 (m, 2H), 8.52 (s, 1H), 8.75 (s, 1H).
MS (ES+): m/z 538 (M+H)+.
EXAMPLE 173. N-tert-Butyl-3-{5-methyl-2-14-(1-morpholin-4-yl-ethyl)-phenylaminol-. Pvrimidin-4-ylamino}-benzenesulfonamide (Compound CXV) H
NH
C:L L
N N c) CXV
[0351] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(1-morpholin-4-yl-ethyl)-phenylamine (80 mg, 0.39 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.061 mmol) and cesium carbonate (0.26 g, 0.80 mmol) in dioxane (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 *C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).
[0352] 1H NMR (500 MHz, DMSO-d6): 5 1.12 (s, 9H), 1.25 (d, J= 6.6 Hz, 3H), 2.13 (s, 3H), 2.20-2.30 (m, 2H), 2.30-2.40 (m, 2H), 3.24 (q, J= 6.6 Hz, 111), 3.54 (t, J= 4.4 Hz, 4H), 7.10 (d, J= 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.55 (s, 1H), 7.57 (d, J= 8.5 Hz, 2H), 7.93 (s, 1H), 8.09 (s, 1H), 8.15 (d, J= 7.7 Hz, 1H), 8.57 (s, 1H), 8.92 (s, 1H). MS
(ES+): nilz 525 (M+H)+.
EXAMPLE 174. N441H-Indo1-4-y1)-5-methyl-N2-(4-(4-methylpiperazin-1-y1)phenyl)pyrirnidine-2,4-diamine (Compound CXVI) HN
IP NH
NN
CXVI
[0353] A mixture of intermediate 32 (270 mg, 0.9 mmol), 4-bromo-1H-indole (196 mg, 0.9 mmol), Pd2(dba)3 (91 mg, 0.09 mmol), Xantphos (157 mg, 0.27 mmol) and cesium carbonate (1.2 g, 3.6 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacua The residue was purified by HPLC to afford the title compound (55 mg of HCI salt, 14%) as a white solid.
[0354] IHNMR (500 MHz, DMSO-d6): 5 2.22 (s, 3H), 2.79 (d, J= 4.3 Hz, 3H), 2.98-3.03 (m, 2H), 3.08-3.14 (in, 2H), 3.46-3.48 (m, 2H), 3.64-3.66 (m, 2H), 6.35-6.36 (in, 1H), 6.63 (br d, J= 8.0 Hz, 1H), 6.98 (d, J¨ 9.1 Hz, 2H), 7.05 (d, J= 7.4 Hz, 1H), 7.16 (t, J= 7.6 Hz, 1H), 7.36 (t, J= 2.8 Hz, 2H), 7.43 (d, J= 8.0 Hz, 1H), 7.86 (s, 1H), 10.07 (s, 1H), 10.27 (s, 1H), 11.00 (br s, 1H), 11.38 (s, 1H), 12.16 (br s, H). MS (ES+): m/z 414 (M+H)+.
EXAMPLE 175. 2-Chloro-5-methyl-N-(2,3-dimethylphenyl)pyrimidin-4-amine (Intermediate 61) lel NH
N
CI
[0355] A mixture of 2-chloro-5-methylpyrimidin-4-amine (143.6 mg, 1 mmol), 1-bromo-2,3-dimethylbenzene (222 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (174 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (150 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in Et0Ac (10 mL) and added hexanes (100 mL). The solid was collected by filtration and washed with hexanes to afford the crude title compound as a yellow solid.
EXAMPLE 176. 5-Methyl-N4-(2,3-dimethylphenyI)-N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (Compound CXVII), N (3' I NH
N
CXVII
[0356] A mixture of intermediate 61 (1.0 mmol) and tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (292.4 mg, 1.0 mmol) were suspended in acetic acid (10 mL) and heated at 100 C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (105 mg of HC1 salt, 24%) as a yellow solid.
[0357] 1H NMR (500 MHz, DMSO-do): 8 1.76-1.83 (m, 2H), 2.03 (s, 3H), 2.05-2.09 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 3.02-3.05 (m, 2H), 3.18 (br s, 2H), 4.53-4.56 (m, 1H), 6.72 (d, J= 8.5 Hz, 2H), 7.11-7.14 (m, 3H), 7.19-7.24 (m, 2H), 7.87 (s, 1E), 9.06 (br s, 1H), 9.13 (br s, 1H), 9.92 (s, 1H), 10.43 (s, 1H). MS (ES+): in/z 404 (M+H)+.
EXAMPLE 177. /V144-Chloro-3,5-dimethylpheny1)-5-methyl-N2-(4-(4-methylpiperazin-1-yl)phenybpyrimidine-2,4-diamine (Compound CXVIII) CI is N
NH
N N
N
CX VIII
[0358] A mixture of intelinediate 32 (240 mg, 0.8 mmol), 5-bromo-2-thloro-1,3-dimethylbenzene (212 mg, 0.96 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (170 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (63 mg of HC1 salt, 17%) as a white solid.
[0359] IHNMR (500 MHz, DMSO-d6): 5 2.15 (s, 3H), 2.17 (s, 3H), 2.80 (d, J=
4.5 Hz, 3H), 3.06-3.14 (m, 4H), 3.48-3.52 (m, 2H), 3.75-3.77 (m, 2H), 6.93 (d, J= 8.9 Hz, 2H), 7.29 (d, J= 8.9 Hz, 2H), 7.46 (s, 2H), 7.90 (s, 1H), 9.65 (s, 1H), 10.49 (s, 1H), 11.13 (br s, 2H).
MS (ES+): inlz 437 (M+H)+.
EXAMPLE 178. N2-(4-(2-(Pyrrolidin-1-vbethoxy)phenv1)-10-(3-tert-butylpheny1)-5-methyl-pyrimidine-2,4-diamine (Compound CXIX) N
I
N
CXIX
[0360] A mixture of intermediate 41 (365 mg, 1.32 mmol) and 4-(2-(pyrro1idin-1-yl)ethoxy)benzenamine (410 mg, 1.98 mmol) were suspended in acetic acid (20 mL) and heated at 100 C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (127 mg of HC1 salt, 20%) as a white solid.
[0361] 1HNMR (500 MHz, DMSO-d6): 6 1.89-1.91 (m, 2H), 1.98-2.02 (m, 2H), 2.17 (s, 3H), 3.07-3.12 (m, 2H), 3.52-3.57 (m, 4H), 4.32 (t, J 4.8 Hz, 2H), 6.90 (d, J=
8.9 Hz, 2H), 7.29-7.38 (in, 4H), 7.43-7.44 (m, 1H), 7.48 (d, 7.9 Hz, 1H), 7.89 (s, 1H), 9.75 (s, 1H), 10.51 (s, 1H), 11.07 (br, 1H). MS (ESI+): in/z 446 (M+H)+.
EXAMPLE 179. N2-(4-(2-(Pyrrolidin-l-yl)ethoxy)pheny1)44-(4-(3-tert-butylphenyinmino)-5-methylpyrimidin-2-y1)-5-methylpyrimidine-2,4-diamine (Compound CXX1 qiir NH
"N
I
CXX
[0362] A mixture of intermediate 41 (210 mg, 0.67 mmol), intermediate 38 (185 mg, 0.67 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 g, 2.4 mmol) were suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (94 mg of HC1 salt, 24%) as a yellow solid.
[0363] 1H NMR (500 MHz, DMSO-d6): 6 1.29 (s, 9H), 1.84-1.88 (m, 2H), 1.94-2.01 (m, 2H), 2.14 (s, 3H), 2.27 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.56 (m, 4H), 4.29 (t, J-- 4.9 Hz, 2H), 6.97 (d, J= 9.1 Hz, 2H), 7.27 (d, J= 8.6 Hz, 2H), 7.34 (t, J¨ 7.9 Hz, 2H), 7.57 (t, J-1.9 Hz, 2H), 7.65 (d, J= 9.1 Hz, 1H), 7.72 (d, J¨ 8.6 Hz, 2H), 8.15 (s, 1H), 8.39 (s, 1H), 9.82 (s, 1H), 10.21 (br s, 1H), 10.68 (hr s, 1H), 10.93 (hr s, 1H). MS (ES+):
tn/z 553 (M+H)+.
EXAMPLE 180. 5-Methyl-N244-(4-methyl-piperazin-1-y1)-phenyll-N4-[3-(piperidine-sulfony)-phenyll-pyrimidine-2,4-diamine (Compound cxxi) o,s/Pd r la NH
N N'') CXXI
[0364] A mixture of intermediate 32 (150 mg, 0.5 mmol), 1-(3-bromo-benzenesulfony1)-piperidine (152 mg, 0.5 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and cesium carbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (84 rng of HC1 salt, 37%) as a white solid.
[0365] 1H NMR (500 MHz, DMSO-d6): 8 1.30-1.34 (m, 2H), 1.50-1.55 (in, 4H), 2.17 (s, 3H), 2.81 (d, J= 4.5 Hz, 311), 2.88 (t, J= 5.3 Hz, 4H), 3.04-3.16 (m, 4H), 3.47-3.51 (m, 2H), 3.75-3.77 (m, 211), 6.33-6.34 (m, 1H), 6.95 (d, J= 9.0 Hz, 2H), 7.25 (d, J=
9.0 Hz, 2H), 7.56-7.63 (m, 2H), 7.83 (t, J= 1.7 Hz, 111), 7.92 (s, 1H), 8.05 (d, J= 9.3 Hz, 1H), 9.94 (s, 1H), 10.38 (s, 1H), 10.88 (br s, 1H). MS (ES+): rez 522 (M+H)+.
EXAMPLE 181. 5-Methyl-N2-14-(4-methyl-piperazin-1-y1)-phenyll-/V4-[3-(2-metlwl-piperidine-1-sulfony)-phenyll-pyrimidine-2,4-diamine (Compound CXXII) NH
---ACN N') CXXII
[0366] A mixture of intermediate 32 (161 mg, 0.54 mmol), 1-(3-bromo-benzenesulfony1)-2-methyl-piperidine (172 mg, 0.54 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and cesium carbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (10 mg of HC1 salt, 3%) as a white solid.
[0367] 1H NMR (500 MHz, DMSO-d6): 6 0.98 (d, J= 6.9 Hz, 311), 1.15-1.21 (m, 111), 1.36-1.40 (m, 311), 1.47-1.53 (m, 211), 2.18 (s, 3H), 2.80 (d, J= 4.5 Hz, 3H), 2.94-2.99 (m, 1H), 3.05-3.16 (m, 411), 3.47-3.49 (m, 211), 3.59-3.61 (m, 211), 3.73-3.76 (m, 2H), 4.08-4.10 (m, 1H), 6.93 (d, J= 8.9 Hz, 2H), 7.25 (d, J 8.9 Hz, 211), 7.58 (t, J= 8.0 Hz, 111), 7.65 (d, J
= 8.0 Hz, 1H), 7.92 (d, J = 7.1 Hz, 211), 7.96 (br, 111), 9.95 (s, 111), 10.45 (s, 111), 11.00 (br s, 111). MS (ES+): in/z 536 (M+H)+.
EXAMPLE 182. N-Cyclopenty1-3-{5-methy1-2-[4-(4-methyl-piperazin-1-y1)-phenylamino]-pyrimidine-4-ylaminol-benzenesulfonamide (Compound CXXIII) NH N-N') I
N
CXXIII
[0368] A mixture of intermediate 32 (229 mg, 0.78 mmol), 3-bromo-N-cyclopentyl-benzenesulfonamide (280 mg, 0.92 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (130 mg of HC1 salt, 25%) as a white solid.
[0369] 1HNMR (500 MHz, DMSO-d6): 6 1.27-1.36 (m, 4H), 1.36-1.58 (m, 4H), 2.18 (s, 3H), 2.80 (d, J= 4.6 Hz, 3H), 3.05-3.15 (m, 4H), 3.36-3.42 (m, 1H), 3.47-3.49 (m, 2H), 3.74-3.76 (m, 2H), 6.94 (d, J= 8.7 Hz, 2H), 7.26 (d, J= 8.9 Hz, 2H), 7.59 (t, J=
8.0 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.75(d, J= 7.1 Hz, 2H), 7.92 (br, 2H), 7.93 (br, 1H), 9.96 (s, 1H), 10.45 (s, 1H), 11.98 (br s, 1H). MS (ES+): m/z 522 (M+H)+.
EXAMPLE 183. 5-Methyl-N2-14-(4-methyl-piperazin-1-y1)-pheny11-1V4-13-(pyrrolidine-1-sulfony) phenyll-pyrimidine-2,4-diamine (Compound CXXIV) 0---zsLN
NH
N N') N
CXXIV
[0370] A mixture of inten-nediate 32 (298 mg, 1.0 mmol), 1-(3-bromo-benzenesulfony1)-pyrrolidine (360 mg, 1.24 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue Was purified by HPLC to afford the title compound (200 mg of HC1 salt, 37%) as a white solid.
[0371] 1H NMR (500 MHz, DMSO-d6): 8 1.61-1.65 (in, 4H), 2.19 (s, 3H), 2.80 (br, 3H), 3.06-3.16 (in, 10H), 3.74-3.77 (br, 2H), 6.94 (d, J= 9.0 Hz, 2H), 7.26 (d, J=
9.0 Hz, 2H), 7.60 (t, J= 8.0 Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.91 (t, J= 1.7 Hz, 1H), 7.93 (s, 1H), 8.05 (d, J= 7.5 Hz, 1H), 9.95 (s, 1H), 10.43 (s, 1H), 11.07 (br s, 1H). MS (ES+):
nilz 508 (M+H)t EXAMPLE 184. /V4-[3-(2õ5-Dimethyl-pyrrolidine-1-sulfony1)-phenylf-5-methyl-N2-(4-methyl-piperazin-l-y1)-phenyll-pyrimidine-2,4-diamine (Compound CXXV) N
I
N
CXXV=
[0372] A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-(3-bromo-benzenesulfony1)-- 2,5-dimethyl-pyrrolidine (318 mg, 1.0 mmol), Pd2(dba)3 (92 mg, 0.1 I-rump, Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (100 mg of HC1 salt, 17%) as a white solid.
[0373] 11-1 NMR (500 MHz, DMSO-d6): 8 1.26 (s, 3H), 1.27 (s, 3H), 1.45-1.48 (m, 4H), 2.19 (s, 3H), 2.80 (d, J= 4.6 Hz, 3H), 3.06-3.15 (m, 4H), 3.47-3.50 (m, 2H), 3.60-3.64 (m, 2H), 3.74-3.76 (in, 2H), 6.94 (d, J= 9.0 Hz, 2H), 7.25 (d, J= 9.0 Hz, 2H), 7.59 (t, J¨ 8.0 Hz, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.93 (br, 2H), 8.02 (br, 1H), 9.97 (s, 1H), 10.47 (s, 1H), 11.07 (br s, 1H). MS (ES+): m/z 536 (M+H)4-.
EXAMPLE 185. N-tert-Buty1-3-1-5-methy1-2-(4-piperazin-1-y1-pheny1amino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXVI1 r, /0 Liz7S-/-NH
NH
lei NH
N
CXXVI
[0374] A mixture of intermediate 33 (355 mg, 1.0 mmol), tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (278 mg, 1.0 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in CH202 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH was added. The organic layer was separated and aqueous was extracted with CH2C12 (10 mL x 2). The combined organic layers were dried (Na2SO4).
The solvent was removed in vacuo. The residue was purified by HPLC to afford the title compound (62 mg, 12%) as a white solid.
[0375] 1H NMR (500 MHz, DMSO-d6): 5 1.10 (s, 9H), 2.18 (s, 3H), 3.20 (br, 4H), 3.33 (br, 4H), 6.94 (d, J= 9.0 Hz, 2H), 7.25 (d, J= 9.0 Hz, 2H), 7.57 (t, J= 8.0 Hz, 1H), 7.63 (s, 1H), 7.71 (d, J= 8.1 Hz, 1H), 7.87 (br, 1H), 7.92 (br, 1H), 7.96 (br, 1H), 9.30 (br, 1H), 9.96 (s, 1H), 10.46 (s, 1H). MS (ES+): m/z 496 (M+H)+.
EXAMPLE 186. N-tert-Buty1-3-(2-14-1-4-(2-hydroxy-ethyl)-piperazin-1-y11-phenylaminol-f5-methyl-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXVII) * NH NOH
N N
NN
CXXVII
[0376] The above-described compound CXXVI (31mg, 0.06 mmol) was dissolved in DMF (10 mL) followed by adding 2-bromoethanol (16 mg, 0.13 mmol) and diisopropylethylamine (33 mg, 0.25 mmol). The mixture was stirred for 48 h at room temperature. Solvent was removed in vacuo and residue was dissolved in Et0Ac (20 mL).
The solution was washed with saturated NaHCO3 and brine. The combined organic layers were dried and concentrated until 2 mL solution followed by adding Et20 (20 mL). The solid was collected by centrifugation and transferred to its HC1 salt (10.7 mg, 30%).
[0377] 1H NMR (500 MHz, DMSO-d6): 8 1.09 (s, 9H), 2.17 (s, 3H), 3.12-3.23 (in, 4H), 3.56-3.60 (m, 2H), 3.69-3.74 (m, 2H), 3.83 (br, 2H), 4.13 (br, 2H), 6.94 (d, J= 9.0 Hz, 2H), 7.25 (d, J= 9.0 Hz, 2H), 7.57 (t, J= 8.0 Hz, 1H), 7.63 (s, 1H), 7.71 (d, J=
8.1 Hz, 1H), 7.87 (br, 1H), 7.93 (br, 1H), 7.95 (br, 1H), 9.98 (s, 1H), 10.53 (s, 1H), 10.75 (br, 1H). MS (ES+):
m/z 540 (M+H)+.
EXAMPLE 187. N-tert-Butv1-345-methvi-2-(3-piperazin-1-0-phenylamino)-pyrimidin-4-vlaminol-benzenesulfonamide (Compound CXXVIIII
\<"
NH
õL
N
H NH
CXXVIII
[0378] A mixture of intermediate 33 (240 mg, 0.67 mmol), tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (166 mg, 0.6 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in CH2C12 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH was added. The organic layer was separated and aqueous was extracted with CH2C12 (10 mL x 2). The combined organic layers were dried (Na2SO4).
The solvent was removed in vacuo. The residue was purified by HPLC to afford the title compound (18 mg, 6%) as a white solid.
[0379] 11-1NMR (500 MHz, DMSO-d6): 5 1.10 (s, 9H), 2.19 (s, 3H), 3.17 (br, 4H), 3.27-3.29 (m, 4H), 6.80 (d, J= 8.1 Hz, 1H), 6.87 (br, 1H), 6.96 (d, J= 8.1 Hz, 1H), 7.16(t, J= 8.1 Hz, 1H), 7.53 (t, J= 8.3 Hz, 1H), 7.61 (s, 1H), 7.70 (d, J= 7.8 Hz, 1H), 7.94 (br, 3H), 9.19 (br, 2H), 9.93 (s, 1H), 10.48 (s, 1H). MS (ES+): m/z 496 (M+H)+.
EXAMPLE 188. N-tert-Butv1-342-{3-[4-(2-hydroxy-ethyl)-piperazin-1-y1]-phenylaminol-[5-methyl-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXIX) n /0 H
NH
N
N OH
CXXLX
[0380] The above-describeed compound CXXVI (12mg, 0.024 mmol) was dissolved in DMF (10 mL) followed by adding 2-bromoethanol (6.1 mg, 0.048 mmol) and diisopropylethylamine (12 mg, 0.092 mmol). The mixture was stirred for 48 h at room temperature. Solvent was removed in vacuo and residue was dissolved in Et0Ac (20 mL).
The solution was washed with saturated NaHCO3 and brine. The combined organic layers were dried and concentrated until 2 mL solution followed by adding Et20 (20 mL). The solid was collected by centrifugation and transferred to its HC1 salt (7 mg, 51%).
[0381] 1H NMR (500 MHz, DMSO-d6): 5 1.09 (s, 9H), 2.19 (s, 3H), 3.12-3.22 (m, 4H), 3.56-3.60 (m, 2H), 3.69-3.74 (m, 2H), 3.81 (br, 2H), 4.12 (br, 2H), 6.80 (br, 1H), 6.88 (br, 1H), 6.96 (br, 1H), 7.16 (br, 1H), 7.57 (br, 1H), 7.60 (s, 1H), 7.69 (d, J=
7.8 Hz, 1H), 7.94 (br, 3H), 9.94 (s, 1H), 10.49 (s, 1H). MS (ES+): m/z 540 (M+H)+.
EXAMPLE 189. N2-(4-(1H-Pyrazol-1-yl)pheny1)-/V4-(3-tert-butylpheny1)-5-methylpyrimidine-2,4-diamine (Compound CXXX) "N
N
CXXX
[0382] A mixture of intermediate 41 (580 mg, 2.1 mmol) and 4-(1H-pyrazol-1-yl)benzenamine (335 mg, 2.1 mmol) were suspended in acetic acid (10 mL) and heated at 100 C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (31 mg, 4%) as a yellow solid.
[0383] 1H NMR (500 MHz, DMSO-d6): 8 1.24 (s, 911), 2.18 (s, 3H), 6.53 (t, J= 2.0 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.38 (t, J= 7.9 Hz, 1H), 7.44 (s, 1H), 7.47 (d, J= 8.2 Hz, 111), 7.50 (d, J- 8.9 Hz, 2H), 7.67 (d, J= 8.9 Hz, 2H), 7.73 (s, 1H), 7.95 (s, 1H), 8.43 (d, J= 2.4 Hz, 1H), 9.81 (hr s, 1H), 10.67 (s, 111). MS (ES+): m/z 399 (M+H) .
EXAMPLE 190. M-(7-Chloro-1H-indol-4-y1)-5-methyl-N2-(4-((piperazin-1-yl)methyl)pheny1)-pyrimidine-2,4-diamine (Compound CXXXI) HN
CI
"Nii 1\1.
N LNH
CXXXI
[0384] A mixture of intermediate 40 (150 mg, 0.37 mmol), 4-bromo-7-chloro-1H-indole (87 mg, 0.37 mmol), Pd2(dba)3 (38 mg, 0.04 mmol), Xantphos (76 mg, 0.12 mmol) and cesium carbonate (521 mg, 1.6 mmol) were suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in CH2C12 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH
was added. The organic layer was separated and aqueous was extracted with CH2C12 (10 mL
x 2). The combined organic layers were dried (Na2SO4). The solvent was removed in vacuo.
The residue was purified by HPLC to afford the title compound (26 mg, 15%) as a white solid.
[0385] 1H NMR (500 MHz, DMSO-d6): 5 2.21 (s, 3H), 3.30 (br, 4H), 3.50 (br, 4H), 4.42 (br, 2H), 6.91 (s, 1H), 7.11 (d, J= 8.3 Hz, 1H), 7.40 (d, J= 7.5 Hz, 1H), 7.42 (t, J= 2.7 Hz, 1H), 7.70 (br, 4H), 8.03 (s, 1H), 9.87 (br, 1H), 9.95 (s, 1H), 10.64 (s, 1H), 11.64 (s, 1H). MS
(ES+): m/z 448 (M+H)+.
EXAMPLE 191. A1443-tert-Butylpheny1)-5-methyl-N2-(4-(2-methyl-1H-imidazol-1-ybphenv1)-pyrirnidine-2,4-diamine (Compound CXXXII) N
N
CXXXII
[0386] A mixture of intetinediate 41 (180 mg, 0.65 mmol) and 4-(2-methy1-1H-imidazol-1-yl)benzenamine (113 mg, 0.65 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (78 mg of HC1 salt, 27%) as a white solid.
[0387] 1H NMR (500 MHz, DMSO-d6): 5 1.26 (s, 9H), 2.21 (s, 3H), 2.50 (s, 3H), 7.31-7.36 (m, 1H), 7.40 (t, J= 7.8 Hz, 1H), 7.44 (d, J= 8.9 Hz, 2H), 7.47 (d, 8.0 Hz, 2H), 7.65 (d, J= 8.9 Hz, 2H), 7.75 (d, J= 2.1 Hz, 1H), 7.79 (d, J= 2.1 Hz, 2H), 8.03 (s, 1H), 10.02 (s, 1H), 11.26 (s, 1H). MS (ES+): m/z 413 (M+H)+.
EXAMPLE 192. 4-(4-Methyl-1H-imidazol4-yl)benzenamine (Intermediate 62) N
[0388] To a solution of 1-fluoro-4-nitrobenzene (1.7 g, 12 mmol) in DMF
(100 mL) was added 4-methyl-1H-imidazole (0.82 g, 10 nunol) and K2CO3 (11g, 80 mmol). The mixture was heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with brine (100 mL x 2). The organic layer was dried and concentrated. The solid was dissolved in Me0H and bubbled with Ar for 2 min. before adding 10% Pd-C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (1.5 g, 87%) as brown solid.
EXAMPLE 193. /V4-(3-tert-Butylpheny1)-5-methyl-N2-(4-(4-methyl-1H-imidazol-1-yl)phenyl) pyrimidine-2,4-diamine (Compound CXXAIII) la NH
(1r I
N
CXXXIII
[0389] A mixture of intennediate 41 (318 mg, 1.15 mmol) and intermediate 62 (200 mg, 1.15 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacua. The residue was purified by HPLC to afford the title compound (66 mg of HC1 salt, 20%) as a white solid.
[0390] 1H NMR (500 MHz, DMSO-d6): 6 1.26 (s, 9H), 2.19 (s, 3H), 2.36 (s, 3H), 7.30 (d, J= 7.9 Hz, 114), 7.41 (d, J= 7.9 Hz, 1H), 7.44 (t, J= 1.8 Hz, 1H), 7.54 (d, J=
7.9 Hz, 1H), 7.59 (d, J= 9.0 Hz, 2H), 7.68 (d, J= 9.0 Hz, 2H), 7.94 (s, 1H), 7.99 (s, 1H), 9.53 (d, J= 1.3 Hz, 1H), 9.72 (br s, 1H), 10.81(br s, 1H). MS (ES+): in/z 413 (M+H)+.
EXAMPLE 194. tert-Butyl 4-(4-aminophenyl)piperidine-1-earboxylate (Intermediate .3_1 NBoc [0391] To a solution of 4-(4-nitrophenyl)piperidine (412 mg, 2 mmol) in CH2C12 (100 mL) was added di-tert-butyl carbonate (480 mg, 2.2 mmol) and N,N-dimethylpyridin-4-amine (50 mg, 0.4 mmol). The mixture was stirred for 20 h at room temperature.
The mixture was added saturated NaHCO3 (100 mL). The organic layer was separated and aqueous was extracted with CH2C12 (50 mL x 2). The combined organic solution was dried and concentrated in vacuo. The residue was dissolved in Me0H and bubbled with Ar for 2 mm. before adding 10% Pd-C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacua to afford title compound (460 mg, 83%) as white solid.
EXAMPLE 195. /V4-(3-tert-Butylpheny1)-5-methyl-N244-(piperidin-4-y1)phenyl)pyrimidine-2,4-diamMe (Compound CXXXIV) NH NH
S
N
CXXXIV
[0392] A mixture of intermediate 41 (170 mg, 0.6 mmol) and intermediate 63 (170 mg, 0.6 mmol) were suspended in acetic acid (10 mL) and heated at 100 C for 4 h.
The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure.
The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (8 mg, 3%) as a white solid.
[03931 NMR (500 MHz, DMSO-d6): 6 1.26 (s, 9H), 1.76-1.88 (m, 4H), 2.17 (s, 3H), 2.76-2.81 (m, 1H), 2.93-3.00 (m, 2H), 3.36-3.40 (m, 2H), 7.07 (d, J= 8.5 Hz, 1H), 7.30-7.36 (m, 4H), 7.44 (s, 1H), 7.46 (d, J= 8.7 Hz, 1H), 7.91 (s, 1H), 8.84 (br s, 1H), 8.92 (br s, 1H), 9.73 (s, 1H), 10.45 (s, 1H). MS (ES+): nilz 416 (M+H)+.
EXAMPLE 196. N4-(3-tert-Butylphenv1)-5-methyl-N2-(4-(1-morpholinoethyl)phenyl)pyrhnidine-2,4-diamine (Compound CXXXV1 N N') CXXXV
[0394] A mixture of intermediate 41 (276 mg, 1.0 mmol) and 4-(1-morpholinoethyl)benzenamine (210 mg, 1.0 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (17 mg of HC1 salt, 4%) as a yellow solid.
[0395] 114 NMR (500 MHz, DMSO-d6): 6 1.26 (s, 9H), 1.66 (d, J= 6.8 Hz, 3H), 2.19 (s, 3H), 2.79 (br, 2H), 2.92 (br, 1H), 3.61-3.64 (m, 2H), 3.77-3.82 (m, 2H), 3.94-3.99 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.42 (t, J= 1.9 Hz, 1H), 7.43 (d, J= 7.8 Hz, 1H), 7.46-7.52 (m, 5H), 7.97 (s, 1H), 9.86 (s, 1H), 10.78 (s, 1H), 11.72(br s, 1H). MS (ES+): ni/z 446 (M+H)+.
EXAMPLE 197. 5-Bromo-2-methyl-benzenesulfonyl chloride (Intermediate 64) CI, la Br 0"0 [0396] Bromide (1.99 g, 11.61 mmol) was stirred vigorously and treated with chlorosulfonic acid (1.55 mL, 23.22 mmol). Once addition was complete, resulting red syrup was heated to 60 C. Reaction TLC after 10 min showed no starting material and reaction was quenched by pouring onto ice. Product was extracted by washing with Et0Ac (2 x 150 mL). Organic phase dried over Na2SO4, filtered and evaporated to yellow oil (2.2g, 70%).
EXAMPLE 198. 5-Bromo-2,N-dimethy1-benzenesu1fonamide (Intermediate 65) NH, Br 0/ \O
[0397] A stirring suspension of intermediate 64 (0.43 g, 1.58 mmol) in DCM (5 mL) was treated with 2.0M methylamine solition in THF (2.4 mL, 4.8 mmol). After 16 h reaction solvents were removed and resulting residue diluted with Et0Ac (150 mL) and washed with water. Organic phase dried over Na2SO4, filtered and evaporated to white solids (0.37 g, 89%).
EXAMPLE 199. 2,N-Dimethy1-545-methyl-244-(2-pyrrolidin-1-yl-ethoxy)-pheny1amino1-pyrimidin-4-y1aminol-benzenesu1fonamide (Compound CXXXVI) NH, 4101 \ NH
0"0 oNo N N
CXXXVI
[0398] A mixture of intermediate 65 (0.14 g, 0.52 mmol), intermediate 38 (0.14 g, 0.43 mmol), Pd2(dba)3 (0.040 g, 0.043 mmol), Xantphos (0.050 g, 0.087 mmol) and cesium carbonate (0.43 g, 1.3 mmol) were suspended in dioxane (10 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.052 g, 24%).
[0399] NMR
(500 MHz, DMSO-d6): 8 1.66-1.70 (m, 4H), 2.08 (s, 3H), 2.43 (d, J = 4.9 Hz, 3H), 2.5 (br s, 4H), 2.78, (t, J= 5.7 Hz), 4.00 (t, J= 5.9 Hz), 6.79 (d, J= 9.0 Hz, 2H), 7.31 (d, J= 9.7 Hz, 1H), 7.42 (q, J= 9.8 Hz, 1H), 7.49 (d, J= 9.0 Hz, 1H), 7.87 (s, 1H), 7.97 (d, J= 2.3 Hz, 1H), 8.07-8.09 (m, 1H), 8.49 (s, 1H), 8.75 (s, 1H). MS (ES+):
ni/z 497 (M+H)+.
EXAMPLE 200. 5-Bromo-N-tert-butyl-2-methyl-benzenesulfonamide ( Intermediate .1 Br \O
[04001 A stirring suspension of intermediate 64 (1.22 g, 4.5 mmol) in DCM (25 mL) was treated with tert-butylamine (1.4 mL, 13.6 mmol). After 16 h, reaction solvents were removed and resulting solids triturated with water. Solids were dried uner vacuum overnight (1.3 g, 94%).
EXAMPLE 201. N-tert-Butv1-542-ehloro-5-methyl-pyrimidin-4-ylamino)-2-methyl-benzenesulfonamide (Intermediate 67) H
Ns NH
0"0 CI
[04011 A
mixture of intermediate 66 (0.90 g, 2.96 mmol), 2-chloro-5-methyl-pyrimidin-4-ylamine (0.33 g, 2.28 mmol), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.264 g, 0.46 mmol) and cesium carbonate (2.2 g, 6.8 mmol) were suspended in dioxane (15 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 15 min.
The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified on silica gel column to afford the title compound as a white solid (0.12 g, 14%).
EXAMPLE 202 N-tert-Buty1-5-12-(4-imidazol-1-yl-phenylamino)-5-methyl-pyrimidin-ylamino1-2-methyl-benzenesulfonamide (Compound CXXXVII) NH N
N N
cxxxva [0402] A mixture of intermediate 67 (0.113 g, 0.31 mmol), 4-imidazol-1-yl-phenylamine (0.059 g, 0.37 mmol), Pd2(dba)3 (0.028 g, 0.03 mmol), Xantphos (0.036 g, 0.06 mmol)- and cesium carbonate (0.3 g, 0.92 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 15 min.
The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.052 g, 24%).
[0403] 1H NMR (500 MHz, DMSO-d6): 5 1.11 (s, 9H), 2.13 (s, 3H), 2.58 (s, 3H), 7.07 (s, 1H), 7.34 (d, J= 8.5 Hz, 1H), 7.42 (d, J= 8.9 Hz, 2H), 7.48 (s, 1H), 7.60 (s, 1H), 7.78 (d, J=
8.9 Hz, 2H), 7.94 (s, 1H), 7.98-8.00 (m, 1H), 8.09 (s, 1H), 8.12 (d, J = 2.3 Hz, 1H), 8.56 (s, 1H), 9.16 (s, 1H). MS (ES+): m/z 492 (M+H)+.
EXAMPLE 203. N-tert-Butv1-3-{5-methy1-244-(pyrrolidine-1-carbony1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXXVIII) /S, NH 0 0"0 40N N LI
CXXXVIII
[0404] A mixture of intatinediate 33 (0.11 g, 0.32 mmol), (4-amino-pheny1)-pyrrolidin-1-yl-methanone (0.072 g, 0.38 mmol), Pd2(dba)3 (0.029 g, 0.032 mmol), Xantphos (0.037 g, 0.063 mmol) and cesium carbonate (0.3 g, 0.95 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C
for 15 min.
The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.040 g, 25%).
[0405] 1H NMR (500 MHz, DMSO-d6): 5 1.11 (s, 9H), 1.8 (br s, 4H), 2.14 (s, 3H), 3.44 (t, J = 6.6 Hz, 4H), 7.38 (d, J = 9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56 (s, 1H), 7.70 (d, J = 9.8 Hz, 2H), 7.98 (s, 1H), 8.08-8.10 (m, 2H), 8.60 (br s, 1H), 9.24 (s, 1H). MS (ES+):
in/z 509 (M+H)+.
EXAMPLE 204. N-tert-Buty1-3-45-methyl-2-14-(morpholine-4-carbony1)-phenylamino1-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXXIX) H
__.N SS
N
CXXXIX
[0406] A mixture of intermediate 33 (0.13 g, 0.37 mmol), (4-amino-pheny1)-morpholin-4-yl-methanone (0.092 g, 0.45 mmol), Pd2(dba)3 (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C
for 15 min.
The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.065 g, 33%).
[0407] NMR (500 MHz, DMSO-d6): 8 1.11 (s, 9H), 2.14 (s, 3H), 3.49 (br s, 4H), 3.59 (br s, 4H), 5.75 (s, 1H), 7.25 (d, J= 9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56 (s, 1H), 7.71 (d, J-9.0 Hz, 2H), 7.98 (s, 1H), 8.06-8.08 (m, 2H), 8.65 (br s, 1H), 9.26 (s, 1H).
MS (ES+): nilz 525 (M+H)+.
EXAMPLE 205. N-tert-Buty1-345-methy1-2-1-4-(piperazine-1-carbony1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXL) H
N
NN L,NH
CXL
[0408] A mixture of intetinediate 33 (0.12 g, 0.33 mmol), 4-(4-amino-benzoy1)-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.45 mmol), Pd2(dba)3 (0.030 g, 0.037 mmol), Xantphos (0.038 g, 0.075 mmol) and cesium carbonate (0.33 g, 1.1 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 15 min. The reaction was decanted and the organic phase concentrated in vacua The residue was purified by silica gel chromatography (25%400%
EtOAc in Hexanes). Product was then treated with 20 mL of 20% TFA solution in DCM.
Solvents then removed by rotary evaporation. Resulting material purified by HPLC to afford the title compound as a white solid (0.045 g, 26%).
[0409] 1H
NMR (500 MHz, DMSO-d6): 5 1.11 (s, 9H), 2.14 (s, 3H), 2.82 (br s, 4H), 3.48 (br s, 4H), 7.24 (d, J= 9.0 Hz, 2H), 7.51-7.53 (m, 2H), 7.55 (s, 1H), 7.71 (d, J= 9.0 Hz, 2H), 7.94 (s, 1H), 8.06-8.08 (m, 2H), 8.65 (br s, 1H), 9.25 (s, 1H). MS (ES+): m/z 524 (M+H)+.
EXAMPLE 206. tert-Butyl 4-(4-(443-methoxyphenylamino)-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-earboxylate (Intermediate 68) O NH
\
I lej NBoc N
[0410] A mixture of 1-bromo-3-methoxybenzene (69.5 pL, 0.56 mmol), intermediate 42 (205 mg, 0.51 mmol), Pd2(dba)3 (23 mg, 0.03 mmol), Xantphos (33 mg, 0.06 mmol) and cesium carbonate (359 mg, 1.10 mmol) in dioxane (3 mL) was irradiated in the microwave at 160 C for 20 min. The reaction mixture was cooled to room temperature, filtered and the filtrate rinsed with DCM and Me0H. The combined liquids were concentrated in vacuo, and .purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a beige solid (215 mg, 83%).
EXAMPLE 207. 3-(2-(4-(Piperidin-4-yloxy)phenylamino)-5-methylpyrimidin-4-ylamino)phenol (Compound CXLI) HO NH
I NH
N
CXLI
[0411] To a mixture of intermediate 68 (215 mg, 0.42 mmol) in DCM (4 mL) was added BBr3 (120 p,L, 1.27 mmol) and stirred at room temperature for 64h. The reaction was quenched with Me0H and concentrated in vacuo. The residue was purified by preparative HPLC and the fractions concentrated in vacuo to afford the TFA salt of the title compound (116 mg, 56%). The TFA salt was taken up in Me0H and passed through SPE PL-MP-Resin cartridges, concentrated in vacuo, triturated with ether, and filtered to provide the title compound as a white solid (31 mg, 69% recovery).
[0412] NMR (500 MHz, DMSO-d6): 8 1.51-1.60 (m, 2H), 1.90-1.98 (m, 2H), 2.07 (s, 3H), 2.70-2.78 (m, 2H), 3.02-3.09 (in, 2H), 4.28-4.36 (m, 1H), 6.48 (dd, J=
8.1, 2.2 Hz ,1H), 6.79 (d, J = 9.1 Hz, 2H), 7.06-7.11 (m, 2H), 7.16 (d, J= 8.5 Hz, 1H), 7.57 (d, J- 9.1 Hz, 2H), 7.82 (s, 1H), 8.08 (s, 1H), 8.73 (s, 1H), 9.27 (br s, 1H). MS (ES+): intz 392 (M+H)+.
EXAMPLE 208. (2-Chloro-5-methyl-pyrimidin-4-y1)-(4-fluoro-3-methoxy-pheny1)-amine (Intermediate 69) '10 SI NH
N
I
CI
[0413] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.2 g, 8.1 mmol), 4-bromo-1-fluoro-2-methoxy-benzene (1.8 g, 8.9 mmol), Pd2(dba)3 (0.74 g, 0.81 mmol), Xantphos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g, 24.2 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (0.3 g, 14%) as a beige solid.
EXAMPLE 209. N4-(4-Fluoro-3-methoxy-pheny1)-5-methyl-N2-14-(2-pyrrolidin-1-0-ethoxy)-phenyli-pyrimidine-2,4-diamine (Compound CXLII) --N- N
CXLII
[0414] A mixture of intelinediate 69 (0.1 g, 0.37 mmol) and 4-(2-pyrrolidin-1-y1-ethoxy)-phenylamine (0.16 g, 0.75 mmol) were suspended in acetic acid (10 mL) and heated to 110 C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.03 g, 17%) as green solids. Ili NMR (500 MHz, DMSO-d6): 8 1.88 (br s, 2H), 2.0 (br s, 2H), 2.15 (s, 3H), 3.08 (br s, 2H), 3.55 (br s, 4H), 3.7 (s, 3H), 4.32 (br s, 2H), 6.9 (d, J= 7.9 Hz, 2H), 7.13 (br s, 1H), 7.21-7.25 (in, 1H), 7.32-7.34 (m, 3H), 7.89 (s, 1H), 9.78 (br s, 1H), 10.48 (br s, 1H), 10.92 (br s, 1H). MS (ES+): m/z 438 (M+H)+.
EXAMPLE 210. (2-Chloro-pyrimidin-4-y1)-(3-methoxy-2-methyl-phenyl)-amine (Intermediate 70) N
I
CI
[0415] A mixture of 3-methoxy-2-methyl-phenylamine (0.68 g, 5 mmol) and 2,4-dichloro-pyrimidine (0.74 g, 5 mmol) were suspended in ethyl alcohol (10 mL) and stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.085 g, 7%) as yellow solids.
EXAMPLE 211. N4-(3-Methoxy-2-methyl-phenyl)-N2-[4-(2-pyrrolidin-1-yl-ethoxv)-pheny11-pyrimidine-2,4-diamine (Compound CXLIII) O NH
N (INNO
CXLIII
[0416] A mixture of intermediate 70 (0.08 g, 0.32 mmol) and 4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine (0.13 g, 0.64 mmol) were suspended in acetic acid (10 mL) and heated to 80 C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.03 g, 17%) as grey solids.
[0417] IFINMR (500 MHz, DMSO-d6): 8 1.89 (br s, 2H), 2.0 (br s, 4H), 3.08 (br s, 2H), 3.4 (br s, 4H), 3.54 (br s, 4H), 3.83 (s, 3H), 4.31 (br s, 2H), 6.86 (br s, 2H), 6.97 (d, J= 8.1 Hz, 2H), 7.26 (t, J= 8.1 Hz 1H), 7.34 (br s, 2H), 7.89 (s, 1H), 9.73 (br s, 1H), 10.62 (br s, 2H), 11.01 (br s, 1H). MS (ES+): tn/z 420 (M+H)+. =
EXAMPLE 212. 4-(4-Acetylamino-benzenesulfony1)-piperidine-1-carboxylic acid tert-butvl ester (Intermediate 711 0 õP
0 fel s N N
[0418] A mixture of 4-(4-bromo-benzenesulfony1)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 9.92 mmol), acetamide (0.88 g, 14.9 mmol), Pd2(dba)3 (0.46 g, 0.49 mmol), Xantphos (0.56 g, 0.99 mmol) and cesium carbonate (9.7 g, 29.8 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and poured onto ice. Resulting yellow solids collected by filtration and dried. Crude product was purified by flash chromatography on silica gel to afford the title compound as a beige solid (3.12 g, 82%).
EXAMPLE 213. 4-(4-Amino-benzenesulfonyI)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 72) 0õp N
H
[0419] A suspension of intermediate 71 (2.6 g, 6.7 mmol) was diluted with 60 mL of Claisen's alkali (88 g KOH dissolved in 63 mL H20 diluted up to 250 mL with Me0H) and heated to 90 C. After 2 h, reaction was removed from heating, cooled to room temperature and diluted with water (50 mL). Grey solids collected by suction filtration, washed with water and dried overnight (2.2 g, 97%).
EXAMPLE 214. N4-(4.-Ch1oro-3-methoxy-pheny1)-5-methy1-N2-14-(piperidine-4-sulfony1)-phenyll-pyrimidine-2,4-diamine (Compound CXLIV).
Cl NH 0\ ,0 (110 =N
-N N H
CXLIV
[0420] A mixture of inten-nediate 31 (0.14 g, 0.51 mmol), intermediate 72 (0.19 g, 0.56 mmol), Pd2(dba)3 (0.046 g, 0.051 rnmol), Xantphos (0.59 g, 0.1 mmol) and cesium carbonate (0.5 g, 1.52 mmol) were suspended in dioxane (8 inL) and microwaved at 160 C
for 15 min.
The reaction mixture was cooled to room temperature and centrifuged down.
Solvents were then decanted and evaporated. Resulting residue was purified by flash chromatography on silica gel to afford the N-protected precursor of title compound. These solids were treated with 20% TFA in DCM solution and immediately evaporated. Residue was dissolved in minimum amount to Et0Ac and added dropwise to large excess of diethyl ether.
Resulting light yellow powder was collected by filtration and dried (0.16 g, 55%).
[0421] 1H NMR (500 MHz, DMSO-d6): 1.61-1.69 (m, 2H), 1.98-2.01 (m, 2H), 2.16 (s, 3H), 2.86 (q, J= 12 Hz, 2H), 3.35 (d, J= 12.6 Hz, 2H), 3.64 (tt, J= 11.7 Hz, J= 3.8 Hz, 1H), 3.79 (s, 3H), 7.34 (dd, J= 8.7 Hz, J= 2.0 Hz, 1H), 7.39-7.41 (m, 2H), 7.6 (d, J= 8.9 Hz, 2H), 7.91 (d, J= 8.9 Hz, 2H), 8.02 (s, 1H), 8.19-8.21 (m, 1H), 8.6-8.63 (m, 1H), 8.89 (br s, 1H). MS (ES+): m/z 488 (M+H)+.
EXAMPLE 215. (4-Chloro-3-methyl-pheny1)-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 73) Cl NH
N CI
[0422] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol), bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8 '1), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g, 7 mmol) were suspended in dioxane (9 mL) microwaved at 160 C for 20 mm. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated.
Resulting residue was purified by flash chromatography on silica gel to afford title compound as yellow solids (0.24 g, 38%).
EXAMPLE 216. /V4-(4-Chloro-3-methyl-pheny1)-5-methyl-N2-[4-(piperidin-4-yloxy)-pheny11-pyrimidine-2,4-diamine (Compound CXLV) CI
NH
N (j NH
-N N
CXLV
[0423] A mixture of intermediate 73 (0.071 g, 0.27 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) were diluted with HOAc (5 mL) and microwaved at 150 C for 15 mm. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.025 g, 22%).
[0424] IHNMR (500 MHz, DMSO-d6): 6 1.76-1.83 (m, 2H), 2.05-2.09 (in, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 3.10 (br s, 2H), 3.16 (br s, 2H), 4.58-4.61 (m, 1H), 6.93 (d, J= 9 Hz, 2H), 7.34-7.39 (m, 3H), 7.43-7.45 (m, 1H), 7.59 (s, 1H), 7.87 (s, 1H), 8.51 (br s, 1H), 8.55 (br s, 1H), 9.38 (br s, 1H), 10.0 (br s, 1H). MS (ES+): mlz 424 (M+H)+.
EXAMPLE 217. N-(3-Bromo-phenyl)-acetamide (Intermediate 74) Br [0425] A solution of 3-bromo-phenylamine (1.04 g, 6 mmol) was treated with DIEA (2.3 mL, 13.3 mmol) and chilled to zero degrees. Acetyl chloride (0.47 mL, 6.7 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to beige solids (1.25 g, 98%).
EXAMPLE 218. N43-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-phenyll-acetamide (Intermediate 75) N CI
NH
[0426] A mixture of 2-ch1oro-5-methyl-pyrimidin-4-ylamine (0.71 g, 4.9 mmol), intermediate 74 (1.25 g, 5.9 mmol), Pd2(dba)3 (0.45 g, 0.49 mmol), Xantphos (0.57 g, 0.98 mmol) and cesium carbonate (4.8 g, 14.7 mmol) were suspended in dioxane (40 mL) refluxed for 18 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.44, 32%).
EXAMPLE 219. N-(3-15-Methy1-2-[4-(piperidin-4-vloxy)-phenylaminol-pyrimidin-4-ylaminol-pheny1)-acetamide (Compound CXLVI) )Lo NH
N-7N1\1 o'"----N1 NH
N N
H
CXLVI
[0427] A mixture of intermediate 75 (0.074 g, 0.27 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) were diluted with HOAc (5 mL) and microwaved at 150 C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.072 g, 62%).
[0428] 1H NMR (500 MHz, DMSO-d6): 8 1.74-1.81 (m, 2H), 2.03-2.07 (m, 5H), 2.15 (s, 3H), 3.09 (br s, 2H), 3.24 (br s, 2H), 4.54-4.57 (m, 1H), 6.85 (d, J- 8.8 Hz, 2H), 7.22 (d, J =
7.7 Hz, 2H), 7.29-7.39 (m, 4H), 7.77 (s, 1H), 7.87 (s, 1H), 8.55 (br s, .1H), 8.60 (br s, 1H), 9.67 (s, 1H), 10.0 (br s, 111), 10.2 (br s, 1H). MS (ES+): nilz 433 (M+H)+.
EXAMPLE 220. N-(3-Bromo-2-methyl-phenyl)-acetamide (Intermediate 76) Br [0429] A solution of 3-bromo-2-methyl-phenylamine (4.1 g, 21.9 mmol) was treated with DIEA (8.4 mL, 48 mmol) and chilled to zero degrees. Acetyl chloride (1.7 mL, 24.1 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to off-white solids. Trituration with hexanes afforded title compound as white solids (4.4 g, 89%).
EXAMPLE 221. N-13-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-2-methyl-phenyll-acetamide (Intermediate 77) NH
N CI
[0430] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.86 g, 5.9 mmol), intermediate 76 (1.6 g, 7.1 mmol), Pd2(dba)3 (0.55 g, 0.59 mmol), Xantphos (0.69 g, 1.2 mmol) and cesium carbonate (5.8 g, 17.8 mmol) were suspended in dioxane (40 mL) refluxed for 16 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.56 g, 32%).
EXAMPLE 222. N-(2-Methyl-3-15-methyl-2-14-(piperidin-4-yloxy)-phenylaminol-PYrimidin-4-ylaminol-phenyl)-acetamide (Compound CXLVII)
MS (ESI+): 539.32 (M+H), r.t. = 2.09 mm.
EXAMPLE 38. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(3-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine TFA salt (Compound VC) CI el (NH
NLN N) XX
[0129] A stirring solution of the above-described intermediate 20 (0.075 g, 0.14 mmol, 1 eq) in DCM (6m1) was treated with TFA (2m1). After 2h, reaction solvents were evaporated and resulting residue triturated with ether to afford the title compound XX as white, hygroscopic solids, TFA salt. (0.05 g, 82%). MS (ESI+): 439.13 (M+H), r.t. =
1.67 mm. 1H
NMR (DMSO-d6): 5 2.17 (s, 3H), 2.89 (bs, 4H), 3.2 (bs, 4H), 3.68 (s, 3H), 3.82 (bs, 3H), 7.16-7.20 (m, 2H), 7.28 (t, J=7.7 Hz, 1H), 7.33 (d, J=2.3Hz, 1H), 7.39 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.49-7.51 (m, 1H), 7.98 (s, 1H), 8.87 (bs, 1H), 9.79 (bs, 1H) 10.57 (bs, 1H).
EXAMPLE 39. 2-(4-(2-(Pyrrolidin-1-yl)ethoxv)nhenylamino)-4-aminopyrimidine-5-earbonitrile (Intermediate 21) Ni H2 NC) .N o [01301 To a solution of 2,4-diaminopyrimidine-5-carbonitrile (135 mg, 1.00 mmol) in 1,4-dioxane (20 mL) was added 1-(2-(4-bromophenoxy)ethyl)pyrrolidine (270 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 174 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL
and hexane (50 mL) was added, the solid was collected by filtration. The crude product was purified by HPLC and afforded the title intenilediate 21 (32 mg, 10%).
EXAMPLE 40. 4-(2.,4-Diehloro-5-methoxypherrylamino)-2-(4-(2-(pyrrolidin-1-ybethoxy)phenvi-amino)pyrimidine-5-earbonitrile (Compound XXI) CI Abi CI
NC-L
I
N
NNS
XXI
[0131] To a solution of the above-described intermediate 21 (32 mg, 0.1 mmol) in 1,4-dioxane (10 mL) was added 1-bromo-2,4-diehloro-5-methoxybenzene (28 mg, 0.11 mmol), Cs2CO3 (97 mg, 0.3mmol), Pd2(dba)3 (7 mg, 0.0074 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 13 mg, 0.022 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was fjltered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by chromatograph (Si02/ CH2C12, then CH2C12 :
Me0H
NH3.1120 = 100: 10: 1) and afforded the title compound XXI (35 mg, 67%). 1H
NMk (500 MHz, DMSO-d6): 1.88-1.90 (m, 2H); 2.00-2.03 (in, 2H); 3.07-3.11 (m, 2H); 3.54-3.56 (m, 4H); 3.81 (s, 3H); 4.25 (br, 2H); 6.68 (br, 2H); 7.32 (br, 2H); 7.33 (s, 1H);
7.75 (s, 1H); 8.50 (s, 1H); 9.73 (br, 1H); 9.94 (br, 1H); 10.60 (br, 1H). MS (El): 499Ø
EXAMPLE 41. 2-(342-(Pyrro1idin-1-y1)ethoxy)pheny1amino)-4-aminopyrimidine-5-carbonitrile (Intermediate 22) NC N
I
N N
[01321 To a solution of 2,4-diaminopyrimidine-5-carbonitrile (145 mg, 1.07 mmol) in 1,4-dioxane (20 mL) was added 1-(2-(3-bromophenoxy)ethyl)pyrrolidine (290 mg, 1.07 mmol), Cs2CO3 (1.43 g, 4.4 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 174 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL
and hexane (50 mL) was added, the solid was collected by filtration. The crude product was purified by HPLC and afforded the title intelinediate 22 (55 mg, 16%).
EXAMPLE 42. 4-(2,4-Dichloro-5-methoxyphenylamino)-2-(3-(2-(pyrrolidin-1-ybethoxy)phenyikamino)pyrimidine-5-carbonitrile (Compound XXII) CI CI
I NCõ),-;
N
NN
XXII
[0133] To a solution of the above-described intermediate 22 (50 mg, 0.15 mmol) in 1,4-- dioxane (10 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (44 mg, 0.17 mmol), Cs2CO3 (200 mg, 0.62 mmol), Pd2(dba)3 (14 mg, 0.015 nunol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 27 mg, 0.05 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na2SO4).
The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXII (6 mg, 8%). 1HNMR (500 MHz, DMSO-d6): 1.87-1.89 (m, 2H); 1.90-2.03 (m, 2H); 3.04-3.08 (m, 2H); 3.52-3.56 (m, 4H); 3.80 (s, 3H); 4.23 (br, 2H);
6.62 (d, J = 6.4 Hz, 2H); 6.97 (br, 1H); 7.14 (br, 2H); 7.34 (s, 1H); 7.74 (s, 1H); 8.54 (s, 1H); 9.70 (br, 1H);
9.95 (br, 1H); 10.83 (br, 1H). MS (El): 499Ø
EXAMPLE 43. 2-Chloro-N-(2,4-dichloro-5-methoxvphenyI)-5-methylpyrimidin-4-amine (Intermediate 23) CI lei CI
Me NH
I
N C
[01341 To a solution of 2-chloro-5-methylpyrimidin-4-amine (44.8 mg, 0.31 mmol) in 1,4-dioxane (20 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (96 mg, 0.37 mmol), Cs2CO3 (408 mg, 1.25 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 70 mg, 0.12 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was used for next reaction without purification.
EXAMPLE 44. N2-(3-(2-(pyrrolidin-l-yflethoxy)pheny1)44-(2,4-diehloro-5-methoxypheny1)-5-methylpyrimidine-2,4-diamine (Compound XXIII) CI Cl Me() NH
N
-IN
N o"
XXIII
[0135] To a solution of the above-described intermediate 23 in 1,4-dioxane (10 mL) was added 3-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (77.3 mg, 0.38 mmol), Cs2CO3 (488 mg, 1.25 mmol), Pd2(dba)3 (28 mg, 0.03 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 53 mg, 0.09 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXIII (25 mg, 15%).
NMR (500 MHz, DMSO-d6): 1.87-1.89 (m, 2H); 1.90-2.03 (m, 2H); 2.18 (s, 3H);
3.04-3.08 (m, 2H); 3.52-3.56 (m, 4H); 3.80 (s, 3H); 4.24 (t, J = 5.0 Hz, 2H); 6.71 (d, J = 7.65 Hz, 1H); 6.91 (s, 1H); 6.96 (d, J = 8.5 Hz, 1H); 7.02 (t, J =8.2 Hz, 1H); 7.37 (s, 1H); 7.83 (s, 1H); .
8.02 (s, 1H); 10.09 (br, 1H); 10.66 (br, 1H); 10.82 (br, 1H). MS (El): 488.2.
EXAMPLE 45. 2-Chloro-N-(3-methoxyphenyI)-5-methylpyrimidin-4-amine (Intermediate 24) Me0 NH
CI
[0136] To a solution of 2-chloro-5-methylpyrimidin-4-amine (320 mg, 2.23 mmol) in 1,4-dioxane (40 mL) was added 1-bromo-3-methoxybenzene (458.5 mg, 2.45 mmol), Cs2CO3 (2.9 g, 8.9 mmol), Pd2(dba)3 (201 mg, 0.22 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 382 mg, 0.66 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine=(1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 24 (500 mg, 90%), was used for next reaction without further purification.
EXAMPLE 46. N2-(4-(2-(pyrrolidin-1-yl)ethoxy)pheny1)-/V4-(3-methoxypheny1)-5-methyl-pyrimidine-2,4-diamine (Compound XXIVA
Me NH
N N
XXIV
[0137] To a solution of the above-described intermediate 24 (240 mg, 0.96 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyn-olidin-l-yl)ethoxy)benzenamine (200 mg, 0.96 mmol), Cs2CO3 (1.3 mg, 4.0 mmol), Pd2(dba)3 (82 mg, 0.09 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 156 mg, 0.27 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by HPLC and afforded the title compound XXIV
(85 mg, 20%). 1H NMR (500 MHz, DMSO-d6): 1.89-1.91 (m, 2H); 1.98-2.05 (m, 2H); 2.16 (s, 3H);
3.07-3.12 (m, 2H); 3.52-3.56 (in, 4H); 3.73 (s, 3H); 4.33 (t, J = 4.5 Hz, 2H);
6.83-6.85 (m, 1H); 6.91 (d, J = 8.8 Hz, 2H); 7.17 (s, 1H); 7.34 (d, J = 8.8 Hz, 2H); 7.41 (t, J = 7.7 Hz, 1H);
7.56 (d, J = 7.7 Hz, 1H); 7.89 (s, 1H); 9.75 (s, 1H); 10.51 (s, 1H); 10.96 (br, 1H). MS (El):
420.2.
EXAMPLE 47. 3-(2-(4-(2-(Pyrrolidin-1-yflethoxy)phenylamino)-5-methylpyrimidin-ylamino)-phenol (Compound XXV) HO el NH
N C)1µ10 I
rµr N
XXV
[0138] To a solution of the above-described compound XXIV (50 mg, 0.1 mmol) in anhydrous CH2C12 (10 mL) was added 1.0 M BBr3 in CH2C12 (0.3 mL, 0.3 mmol).
The mixture was stirred for 3 h at room temperature. The saturated NaHCO3 (20 mL) was added and organic layer was separated. The aqueous was extracted with CH2C12 (3 x 10 mL).
Combined organic solution was dried (Na2SO4). The product was purified by HPLC
and afforded the title compound XXV (17 mg, 35%) as yellow solid. 1HNMR (500 MHz, DMSO-d6): 1.89 (br, 2H); 2.00 (br, 2H); 2.14 (s, 3H); 3.09 (br, 2H); 3.42 (br, 4H); 4.33 (br, 2H); 6.72 (d, J = 7.1 Hz, 1H); 6.91 (d, J = 8.4 Hz, 2H); 6.96 (d, J = 7.6 Hz, 1H); 7.00 (s, 1H);
7.18 (t, J = 8.0 Hz, 1H); 7.38 (d, J = 8.6 Hz, 2H); 7.88 (s, 1H); 9.70 (s, 1H); 9.74 (s, 1H);
10.55 (s, 1H); 11.09 (br, 1H). MS (El): 406.2.
EXAMPLE 48. 2-Chloro-5-methyl-N-(3-nitrophenyl)pyrimidin-4-amine (Intermediate 25_1 h e N
NCI
[0139] To a solution of 2-chloro-5-methylpyrimidin-4-amine (232 mg, 1.61 mmol) in 1,4-dioxane (40 mL) was added 1-bromo-3-nitrobenzene (359 mg, 1.78 mmol), Cs2CO3 (2.1 g, 6.4 mmol), Pd2(dba)3 (146 mg, 0.16 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 278 mg, 0.48 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The Organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 25, was used for next reaction without further purification.
EXAMPLE 49. N2-(442-(pyrrolidin-1-ybethoxy)pheny1)-5-methyl-/V4-(3-nitrophenybpyrimidine-2,4-diamine (Compound XXVI) N
XXVI
[0140] To a solution of the above-described intermediate 25 in 1,4-dioxane (40 mL) was added 4-(2-(pyrrolidin-l-yl)ethoxy)benzenamine (367 mg, 1.78 mmol), Cs2CO3 (2.1 g, 6.4 mmol), Pd2(dba)3 (146 mg, 0.16 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 218 mg, 0.48 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXVI (51 mg, 7%).
1H NMR (500 MHz, DMSO-d6): 1.89-1.92 (m, 2H); 1.98-2.05 (m, 2H); 2.21 (s, 3H);
3.10-3.12 (m, 2H); 3.52-3.57 (m, 4H); 4.33 (t, J = 4.8 Hz, 2H); 6.90 (d, J = 8.9 Hz, 2H); 7.32 (d, J
= 8.9 Hz, 2H); 7.67 (t, J = 8.2 Hz, 1H); 7.99 (s, 1H); 7.56 (dd, J = 8.4 Hz, J
= 1.8 Hz, 1H);
8.09 (d, J = 7.4 Hz, 1H); 8.45 (s, 1H); 10.14 (s, 1H); 10.60 (s, 1H); 11.17 (br, 1H). MS (El):
435.2.
EXAMPLE 50. 4-(2-Chloro-5-methylpyrimidin-4-ylamino)-2-ehlorobenzonitrile (Intermediate 26) CI NH
I
CI
[01411 To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-2-chlorobenzonitrile (217 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 26, was used for next reaction without further purification.
EXAMPLE 51. 4-(2-(442-(pyrrolidin-1-yflethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)-2-ehlorobenzonitrile (Compound XXVII) NC
CI NH
0,No , N N
XXVII
[01421 To a solution of the above-described intermediate 26 (140 mg, 0.5 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (113 mg, 0.55 mmol), Cs2CO3 (660 mg, 2.0 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 87 mg, 0.15 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by HPLC and afforded the title compound XXVII
(11.5 mg, 5%) as a yellow solid. IHNMR (500 MHz, DMSO-d6): 1.89-1.92 (m, 2H);- 1.98-2.05 (m, 2H); 2.20 (s, 3H); 3.08-3.13 (m, 2H); 3.56-3.59 (m, 4H); 4.36 (t, J = 4.9 Hz, 2H); 7.03 (d, J =
9.0 Hz, 2H); 7.40 (d, J = 9.0 Hz, 2H); 7.87 (br, 1H); 7.92 (d, J = 8.6 Hz, 1H); 8.03 (s, 1H);
8.16 (s, 1H); 9.82 (br, 1H); 10.37 (br, 1H); 10.90 (br, 1H). MS (El): 449.1.
EXAMPLE 52. N2-(442-(pyrrolidin-l-yOethoxy)pheny1)-5-methyl-/V4-p-tolylpyrimidine-2,4-diamine (Compound XXVIII1 NH
N
I
N
XXVIII
[0143] To a solution of the above-described intermediate 11 (50 mg, 0.16 nunol) in 1,4-dioxane (20 mL) was added 1-bromo-4-methylbenzene (28 mg, 0.16 mmol), Cs2CO3 (210 mg, 0.64 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 18 mg, 0.03 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXVIII (15.7 mg, 6%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.85-1.89 (m, 2H); 1.96-2.01 (m, 2H);
2.12 (s, 3H); 2.31 (s, 3H); 3.04-3.08 (m, 2H); 3.51-3.55 (m, 4H); 4.32 (br, 2H); 6.89 (br, 2H); 7.18 (br, 2H); 7.31 (br, 2H); 7.41 (br, 2H); 7.84 (s, 1H); 9.71 (s, 1H); 10.46 (s, 1H); 11.13 (br, 1H). MS (El): 404.2.
=
EXAMPLE 53. N2-(4-(2-(pyrrolidin-l-ybethoxy)pheny1)-N4-(4-chloro-3-methylpheny1)-5-methylpyrimidine-2,4-diamine (Compound XXIX) cl NH
XXIX
[0144] To a solution of the above-described intermediate 11 (80 mg, 0.25 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-l-chloro-2-methylbenzene (63 mg, 0.30 mmol), Cs2CO3 (326 mg, 1.0 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 36 mg, 0.06 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound XXIX (17.5 mg, 15%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.85-1.89 (m, 2H); 1.96-2.01 (m, 2H);
2.12 (s, 3H); 2.25 (s, 3H); 3.04-3.08 (m, 2H); 3.51-3.55 (m, 4H); 4.32 (br, 2H); 6.91 (br, 2H); 7.04 (br, 1H); 7.31 (br, 1H); 7.41 (br, 2H); 7.58 (s, 1H); 7.89 (br, 1H); 9.75 (s, 1H); 10.54 (s, 1H);
11.13 (br, 1H). MS (El): 438.1.
EXAMPLE 54. N-(4-(2-(pyrrolidin-1-ybethoxylpheny1)-4-benzy1-5-methylpyrimidin-amine (Compound ,00() N CriLD
N N
XXX
[0145] To a solution of 4-benzy1-2-chloropyrirnidine (286 mg, 1.4 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (288 mg, 1.4 mmol), Cs2CO3 (1.82 g, 5.6 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 173 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound VCX (42 mg, 10%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.89 (br, 2H); 2.00 (br, 2H); 3.09 (br, 2H);
3.54 (br, 4H); 4.31 (br, 2H); 6.71 (d, J = 5.0 Hz, 1H); 6.93 (d, J = 8.8 Hz, 2H); 7.24 (m, 1H);
7.32 (m, 4H); 7.62 (d, J = 8.8 Hz, 2H); 8.32 (d, J = 5.0 Hz, 1H); 9.66 (s, 1H); 10.92 (br, 1H).
MS (E1): 375.2.
EXAMPLE 55. 44(1H-indo1-4-yl)methyl)-N-(4-(2-(pyrrolidin-1-yllethoxy)pheny1)-5-methylpyrimidin-2-amine (Compound XXXI) HN
NH
N
N
VOCI
[0146] To a solution of the above-described intermediate 11 (460 mg, 1.46 mmol) in 1,4-dioxane (20 mL) was added 4-bromo-1H-indole (288 mg, 1.46 mmol), Cs2CO3 (1.95 g, 6.0 mmol), Pd2(dba)3 (128 mg, 0.14 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 243 mg, 0.42 mmol). The mixture was heated under reflux for overnight under Ar. The solid was filtered off. The solvent was removed in vacuo. The crude product was purified by HPLC and afforded the title compound 300(1 (66 mg, 10%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.87 (br, 2H); 1.98-2.05 (m, 2H);
2.21 (s, 3H); 3.15 (br, 2H); 3.52 (br, 2H); 3.69 (br, 2H); 4.24 (br, 2H); 6.33 (s, 1H);
6.60 (br, 2H);
6.82 (br, 1H); 6.92 (br, 1H); 7.02 (br, 2H); 7.16 (br, 1H); 7.26 (br, 1H);
7.43 (m, 1H); 7.88 (m, 1H); 10.11 (s, 1H); 11.40 (s, 1H). MS (E1): 429.1.
EXAMPLE 56. 2-Chloro-5-metiryl-N-(naphthalen-1-y1)pyrimidin-4-amine (Intermediate 27) MTV
NH
N
[0147] To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 mL) was added 1-bromonaphthalene (227 mg, 1.1 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na9SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title interrnediate 27, was used for next reaction without further purification.
EXAMPLE 57. N-(4-(2-(pyrrolidin-l-ybethoxv)pheny1)-5-methyl-4-(naphthalen-1-y1)pyrimidin-2-amine (Compound XXXII) NH
N
I
N
XXXII
[0148] To a solution of the above-described inteimediate 27 (235 mg, 0.87 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (183 mg, 0.87 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 87 mg, 0.15 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by HPLC and afforded the title compound VOUI
(89 mg, 21%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6): 1.88-1.90 (m, 2H); 1.97-2.03 (m, 2H); 2.30 (s, 3H); 3.03-3.08 (m, 2H); 3.50-3.53 (m, 4H); 4.21 (t, J = 4.9 Hz, 2H); 6.50 (d, J =
7.2 Hz, 2H); 6.82 (d, J = 8.6 Hz, 2H); 7.54 (d, J = 7.8 Hz, 2H); 7.57-7.61 (m, 1H); 7.63 (t, J =
7.4 Hz, 1H); 7.89 (d, 3 = 8.3 Hz, 2H); 7.95 (s, 1H); 8.02 (d, 3 = 8.3 Hz, 1H);
8.08 (d, J = 7.7 Hz, 1H); 10.37 (s, 1H); 10.43 (s, 1H); 10.93 (br, 1H). MS (El): 440.1.
EXAMPLE 58. 1-(2-Chloro-5-methylpyrimidin-4-yflisoquinoline (Intermediate 28) I.
N NH
NCI
[0149] To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol) in 1,4-dioxane (40 mL) was added 1-chloroisoquinoline (164 mg, 1.0 mmol), Cs2CO3 (1.3 g, 4.0 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and.4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 28, was used for next reaction without further purification.
EXAMPLE 59. N-(4-(2-(pyrrolidin-l-yl)ethoxy)nheny1)-4-(isocininolin-1-y1)-5-methylpyrimidin-2-amine (Compound Valli) NH
I
N N
Wail [01501 To a solution of the above-described intermediate 28 (90 mg, 0.33 mmol) in 1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-ypethoxy)benzenamine (76 mg, 0.37 mmol), Cs2CO3 (391 mg, 1.2 mmol), Pd2(dba)3 (28 mg, 0.03 mmol), and 4,5-bis(diphenylphosphino)-9,9-ditnethyxanthene (Xant Phos, 52 mg, 0.09 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1 x 50 mL).
The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo.
The crude product was purified by HPLC and afforded the title compound XXXIII
(21 mg, 15%) as a yellow solid. 111NMR (500 MHz, DMSO-d6): 1.64-1.70 (m, 6H); 2.23 (s, 3H);
2.78 (t, J = 5.9 Hz, 2H); 4.04 (t, J = 5.9 Hz, 2H); 6.38 (d, J = 7.2 Hz, 1H);
6.93 (d, J = 9.0 Hz, 2H); 6.97 (d, J = 7.2 Hz, 1H); 7.45 (br, 1H); 7.57 (d, J = 8.8 Hz, 1H); 7.58-7.62 (m, 1H);
7.70-7.78 (m, 2H); 8.04 (s, 1H); 8.75 (d, J = 8.1 Hz, 1H); 9.06 (s, 1H); 9.19 (s, 1H). MS (El):
441.2.
EXAMPLE 60. N2-(4-(2-(pyrrolidin-1-iflethoxy)pheny1)-/V4-(3-.
(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine (Compound XXXIV) 3," NH
N N
)(XXIV
[0151] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (143 mg, 1.0 mmol), 1-bromo-3-(trif1uoromethyl)benzene (225 mg, 1.0 mmol), Pd2(dba)3 (9.0 mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) were suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 15 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in yam . The residue on purification using HPLC gave /V4-(3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine as an off white solid (192 mg, 67%). MS (ESI+): m/z 288 (M+H)+. A mixture of /V4-(3-(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine (28.7 mg, 0.1 mmol) and 4-(2-(pyrrolidin-1-ypethoxy)benzenamine (22 mg, 0.12 mmol) were dissolved in acetic acid (5 mL) and heated under microwave at 150 C for 10 min. The mixture was cooled to room temperature and acetic acid removed under reduced pressure. The residue was purified by HPLC
to afford the title compound LIOCIV as brown solid (16 mg, 35%). 1H NMR (500 MHz, DMSO-d6):
1.65-1.71 (m, 4H), 2.11 (s, 3H), 2.45-2.55 (m, 4H), 2.74 (t, J= 6.0 Hz, 2H), 3.98 (t, J= 6.0 Hz, 2H), 6.76 (d, J= 9.0 Hz, 2H), 7.35 (d, J= 5.1Hz, 1H), 7.45-7.57 (m, 3H), 7.9-7.97 (m, 2H), 8.20 (d, J= 7.6 Hz, 1H), 8.41(s, 1H), 8.85 (s, 1H), nilz 458 (M+H) .
EXAMPLE 61. 2-ehloro-N-(4-(trifluoromethyl)pheny1)-5-methylpyrimidin-4-amine (Intermediate 29) NH
[0152] A suspension of 2-chloro-5-methylpyrimidin-4-amine (159 4, 1.2 mmol), bromo-4-(trifluoromethyl)benzene (150 mg, 1.0 mmol), potassium tert-butoxide (224 mg, 2.0 mmol), Xantphos (120 mg, 0.2 mmol), and palladium acetate (26 mg, 0.1 mmol) was sealed in a microwave reaction tube and irradiated at 160 C for 15 min. The mixture was allowed to cool to room temperature, the solids were filtered using DCM to rinse, and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane to Et0Ac) to afford the title intermediate 29 (128.7 mg, 43%) as a white solid. MS (ESI+): nilz 288 (M+H)+.
EXAMPLE 62. N2-(4-(2-(pyrrolidin-1-ybethoxy)pheny1)-N4-(4-(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine (Compound )00(V) NH
I. CI,No N
XXXV
[0153] A mixture of the above-described intermediates 29 (128 mg, 0.5 mmol) and 6 (212 mg, 1.0 mmol) were suspended in acetic acid (5 mL) and heated at 75 C for 18 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was basified with sat., aq NaHCO3 (50 mL) and extracted with DCM
(2x50 mL). The organic layer was concentrated in vacuo and the crude product purified by reverse phase flash chromatography on C18 (water to CH3CN, 0.1% TFA). The aqueous fractions were neutralized with sat, aq NaHCO3 and extracted with Et0Ac. The organics were concentrated in vacuo and the residue taken up in DCM. HC1 in dioxane was added along with ether and the resulting solid filtered to afford the hydrochloride salt of the title compound XXXV (166 mg, 70%) as a grey solid. Ili NMR (500 MHz, DMSO-d6): 1.80-1.95 (in, 2H), 1.95-2.10 (in, 2H), 2.19 (s, 3H), 3.05-3.20 (in, 2H), 3.55-3.65 (m, 6H), 4.33 (t, J= 4.7 Hz, 2H), 6.97 (d, J= 8.7 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.73 (d, J
= 8.5 Hz, 2H), 7.83 (d, = 8.0 Hz, 2H), 7.94 (s, 1H), 9.92 (hr s, 1H), 10.44 (hr s, 1H), 10.85 (hr s, 1H); MS
(ESI+): ni/z 458.5 (M+14)+.
EXAMPLE 63. Benzo[1,31dioxo1-4-y1-(2-ehloro-5-methyl-pyrimidin-4-171)-amine (Intermediate 30) NH
N
I
CI
[0154] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.4 g, 9.7 mmol), 4-bromo-benzo[1,3]dioxole (2.0 g, 10 rnrnol), Pd2(dba)3 (0.80 g, 0.87 mmol), Xantphos (1.0 g, 1.7 mmol) and cesium carbonate (6.3 g, 19 mmol) was suspended in dioxane (40 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to 50% Et0Ac/hexanes) to afford the title compound (1.0 g, 39%) as a white solid.
1HNMR (500 MHz, DMSO-d6): 6 2.13 (s, 3H), 5.99 (s, 2H), 6.80-6.90 (m, 3H), 8.01 (s, 1H), 8.92 (s, 1H). MS (ES+): m/z 264 (M+H)+.
EXAMPLE 64. /V4-Benzo[1,31dioxo1-4-y1-5-methyl-N2-1442-pyrro1idin-1-yl-ethoxy)-=
phenyll-pyrimidine-2,4-diamine (Compound XXXVI) Aki 0 NH
XXXVI
101551 A mixture of intermediate 30 (0.25 g, 0.95 mmo1) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.40 g, 1.9 mmol) in acetic acid (15 mL) was heated at 100 C for 20 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7 with 10%
NaOH solution. The resulting solution was extracted with Et0Ac (2 x 30 mL) and the organic layer separated. The organic layer was washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by flash chromatography on silica gel (DCM to 20% Me0H/DCM) to afford the title compound (0.14 g, 34%) as a white solid.
[0156] 1H NMR (500 MHz, DMSO-d6): 8 1.65-1.75 (m, 4H), 2.06 (s, 3H), 2.55-2.65 (m, 4H), 2.78-2.88 (m, 2H), 3.98 (t, J= 5.8 Hz, 2H), 5.89 (s, 2H), 6.65 (d, J= 9.0 Hz, 2H), 6.79-6.84 (m, 2H), 6.89 (dd, J=7.7, 1.7 Hz, 1H), 7.45 (d, J= 9.1 Hz, 2H), 7.81 (s, 1H), 8.23 (s, 1H), 8.73 (s, 1H). MS (ES+): m/z 434 (M+H)+.
EXAMPLE 65. /V4-Benzor1,31dioxol-4-y1-5-methyl-N2-[4-(4-methyl-piperazin-1-y1)-pheny11-pyrimidine-2,4-diamine (Compound )(XXVIII
0-\
So NH
N N) I
N
XXXVII
[0157] A mixture of intermediate 30 (0.10 g, 0.38 mmol) and 4-(4-methyl-piperazin-l-y1)-phenylamine (0.12 g, 0.51 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (DCM to 15% Me0H/DCM) to afford the title compound (22 mg, 14%) as a light red solid.
[0158] 11-1 NMR (500 MHz, DMSO-d6): 8 2.06 (s, 3H), 2.21 (s, 3H), 2.44 (t, J= 4.8 Hz, 4H), 2.97 (t, J= 4.9 Hz, 4H), 5.89 (s, 2H), 6.67 (d, J= 9.1 Hz, 2H), 6.80-6.86 (m, 2H), 6.91 (dd, J= 7.6, 1.7 Hz, 1H), 7.41 (d, J= 9.0 Hz, 2H), 7.79 (s, 1H), 8.17 (s, 1H), 8.63 (s, 1H).
MS (ES+): nz/z 419 (M+H)+.
EXAMPLE 66. (4-Chloro-3-methoxv-pheny1)-(2-chloro-5-methyl-avrimidin-4-y1)-amine (Intermediate 31) CI I.
NH
I
CI
[0159] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-bromo-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to 40% Et0Ac/hexanes) to afford the title compound (0.55 g, 55%) as a yellow solid.
[0160] 1H NMR (500 MHz, DMSO-d6): 8 2.18 (s, 3H), 3.85 (s, 3H), 7.35 (dd, J= 8.6, 2.3 Hz, 1H), 7.39 (d, J= 8.7 Hz, 1H), 7.56 (d, J= 2.3 Hz, 1H), 8.09 (d, J= 0.9 Hz, 1H), 8.91 (s, 1H). MS (ES+): in/z 284 (M+H)+.
EXAMPLE 67. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(4-pyrazol-1-ylmethyl-pheny1)-pyrimidine-2,4-diamine (Compound X.XXVIII) , CI dh Me0 NH
"N
1\r N
XXXVIII
[0161] A suspension of intennediate 31 (0.20 g, 0.70 mmol), 4-pyrazol-1-ylmethyl-phenylamine (0.14 g, 0.81 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), Xantphos (50 mg, 0.086 mmol) and cesium carbonate (0.50 g, 1.5 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC.
The fractions were combined and poured into saturated NaHCO3 solution (40 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid was dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.13 g, 44%).
1H NMR (500 MHz, DMSO-d6): 8 2.11 (s, 3H), 3.74 (s, 3H), 5.22 (s, 2H), 6.25 (t, J = 2.1 Hz, 1H), 7.08 (d, J= 8.6 Hz, 2H), 7.27 (d, J= 9.3 Hz, 1H), 7.40-7.45 (m, 3H), 7.60 (d, J¨ 8.6 Hz, 2H), 7.75 (d, J= 1.8 Hz, 1H), 7.91 (s, 1H), 8.36 (s, 1H), 9.04 (s, 1H) MS (ES+): in/z 421 (M+H)+.
EXAMPLE 68. 5-Methyl-N2-[4-(4-methyl-piperazin-1-y1)-phenyl]-pyrimidine-2,4-diamine (Intermediate 321 a N
[0162] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.0 g, 6.9 mmol) and 4-(4-methyl-piperazin-1-y1)-phenylamine (1.5 mL, 7.8 mmol) in acetic acid (15 mL) was heated at 100 C for 2.5 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. After filtration and washed with water, the title compound was obtained as a grey solid (1.3 g, 63%).
[0163] 1H NMR (500 MHz, DMSO-d6): 8 1.88 (s, 3H), 2.21 (s, 3H), 2.21 (s, 3H), 2.44 (t, J= 4.8 Hz, 4H), 3.00 (t, J= 4.8 Hz, 4H), 6.27 (s, 2H), 6.79 (d, J= 9.0 Hz, 2H), 7.57 (d, J=-9.0 Hz, 2H), 7.63 (s, 1H), 8.42 (s, 1H). MS (ES+): nilz 299 (M+H)+.
EXAMPLE 69. 1V444-Chloro-3-methoxy-pheny1)-5-methyl-N244-(4-methyl-piperazin-1-y1)-phenyli-pyrimidine-2õ4-diamMe (Compound X.,XXIX) CI..
Me0 NH
N
=N N
VOCIX
[0164] A suspension of interinediate 32 (0.30 g, 1.0 mmol), 4-bromo-l-chloro-2-methoxy-benzene (0.20 mL, 1.5 mmol), Pd2(dba)3 (50 mg, 0.055 mmol), Xantphos (65 mg, 0.11 mmol) and cesium carbonate (0.70 g, 2.1 mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC.
The fractions were combined and poured into saturated NaHCO3 solution (40 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic 105 t..
layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/5, 30 mL). After filtration, the title compound was obtained as an off white solid (0.20 g, 46%).
[0165] 1H NMR (500 MHz, DMSO-d6): 6 2.09 (s, 3H), 2.21 (s, 3H), 2.45 (t, J=
4.9 Hz, 4H), 3.02 (t, J= 4.9 Hz, 4H), 3.73 (s, 3H), 6.79 (d, J= 9.1 Hz, 2H), 7.27 (d, J= 8.6 Hz, 1H), 7.42-7.47 (m, 3H), 7.49 (d, J= 2.3 Hz, 1H), 7.86 (s, 1H), 8.28 (s, 1H), 8.72 (s, 1H). MS
(ES+): m/z 439 (M+H)+.
EXAMPLE 70. N444-Chloro-3-methoxy-pheny1)-5-methyl-N2-(4-morpholin-4-yl-phenyb-pyrimidine-2,4-diamine (Compound XL) a (61 Me0 IV NH
N) N N
XL
[0166] A mixture of intermediate 31(0.10 g, 0.35 mmol) and 4-morpholin-4-yl-phenylamine (80 mg, 0.45 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by flash chromatography on silica gel (DCM to 10%
Me0H/DCM) to afford the title compound (55 mg, 37%) as a light brown solid.
[0167] NMR (500 MHz, DMSO-d6): 82.10 (s, 3H), 3.00 (t, J= 4.8 Hz, 4H), 3.71-3.76 (m, 7H), 6.80 (d, J= 9.0 Hz, 2H), 7.28 (d, J= 8.6 Hz, 1H), 7.45 (dd, J= 8.7, 2.2 Hz, 1H), 7.47-7.50 (m, 3H), 7.87 (s, 1H), 8.29 (s, 1H), 8.75 (s, 1H). MS (ES+): m/z 426 (M+H)#.
EXAMPLE 71. M-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(4-pyrazol-1-yl-pheny1)-pyrimidine-2,4-diamine (Compound XLI) c, Me() NH
XLI
[0168] A mixture of intefinediate 31 (90 mg, 0.32 mmol) and 4-pyrazol-1-yl-phenylamine (70 mg, 0.44 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture neutralized with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by HPLC. The corrected fractions were combined and concentrated to afford the title compound (40 mg of TFA salt, 24%) as a white solid.
[0169] 1H NMR (500 MHz, DMSO-d6): 5 2.17 (s, 3H), 3.75 (s, 3H), 6.54 (t, J=
1.9 Hz, 1H), 7.30 (d, J= 6.6 Hz, 1H), 7.39 (d, J.= 2.1 Hz, 1H), 7.40 (d, J= 8.6 Hz, 1H), 7.59 (d, 8.9 Hz, 2H), 7.71 (d, J= 8.9 Hz, 2H), 7.73 (d, J= 1.6 Hz, 1H), 7.93 (s, 1H), 8.41 (d, J= 2.5 Hz, 1H), 9.41 (s, 1H), 10.05 (s, 1H). MS (ES+): nilz 407 (M+H)+.
EXAMPLE 72. /0-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(4-piperidin-l-yl-pheny1)-pyrimidine-2,4-diamine [XLII) CI
Me0 NH
NN
XLII
[0170] A mixture of intermediate 31 (0.11 g, 0.39 mmol) and 4-piperidin-1-yl-phenylamine (90 mg, 0.51 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the mixture neutralized with 10% NaOH solution until solid precipitated.
The solid was filtered and then purified by flash chromatography on silica gel (hexanes to 70%
Et0Ac/hexanes)to afford the title compound (10 mg, 6%) as a light brown solid.
[0171] 1HNMR (500 MHz, DMSO-d6): 8 1.48-1.53 (m, 2H), 1.59-1.65 (m, 4H), 2.09 (s, 3H), 3.00 (t, J= 5.4 Hz, 4H), 3.73 (s, 3H), 6.78 (d, J= 9.0 Hz, 2H), 7.27 (d, J= 8.7 Hz, 1H), 7.40-7.47 (m, 3H), 7.50 (d, J= 2.2 Hz, 1H), 7.86 (s, 1H), 8.28 (s, 1H), 8.71 (s, 1H). MS
(ES+): in/z 424 (M+H)+.
EXAMPLE 73. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl- N244-(4-methyl-piperazin-1-ylmethyl)-phenyll-pyrimidine-2,4-diamine (XLIII) =
CI
Me0 IqVI NH
\/11 7)1, NIIN
N N
XLIII
[0172] A suspension of intermediate 31 (50 mg, 0.18 mmol), 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (50 mg, 0.24 mmol), Pd2(dba)3 (10 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol) and cesium carbonate (0.12 g, 0.37 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 10% Me0H/DCM)to afford the title compound (35 mg, 44%) as an off white solid.
[0173] IHNMR (500 MHz, DMSO-d6): 8 2.11 (s, 3H), 2.15 (s, 3H), 2.20-2.45 (m, 8H), 3.35 (s, 2H), 3.75 (s, 3H), 7.07 (d, J= 8.5 Hz, 2H), 7.28 (d, J= 8.5 Hz, 1H), 7.44 (dd, J= 8.7, 2.3 Hz, 1H), 7.47 (d, J= 2.3 Hz, 1H), 7.57 (d, J= 8.5 Hz, 2H), 7.91 (s, 1H), 8.36 (s, 1H), 8.98 (s, 1H). MS (ES+): in/z 453 (M+H)+.
EXAMPLE 74. N4-(4-Chloro-3-methoxy-phenyl)-5-methyl- N244-piperazin-1-yl-pheny1)-pyrimidine-2,4-diamine (Compound XLIV) CI
Me0 NH (NH
\)L N
N N
XLIV
[0174] A mixture of intermediate 31 (0.20 g, 0.70 mmol) and 4-(4-amino-pheny1)-piperazine-1-carboxylic acid tert-butyl ester (0.22 g, 0.79 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C
for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (40 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.10 g, 33%).
[0175] 1HNMR (500 MHz, DMSO-d6): 62.10 (s, 3H), 3.16 (s, 8H), 3.73 (s, 3H), 6.83 (d, J= 9.0 Hz, 2H), 7.29 (d, J= 8.8 Hz, 1H), 7.44 (dd, J= 8.7, 2.1 Hz, 1H), 7.49-7.52 (m, 3H), 7.88 (s, 1H), 8.32 (s, 1H), 8.81 (s, 1H) MS (ES+): m/z 425 (M+H)+.
EXAMPLE 75. N-tert-Buty1-3-{5-methy1-2-[4-(4-methyl-piperazin-1-y1)-phenylamino]-pyrimidin-4-ylaminol-benzenesulfonamide (Compound XLV) H
N
NH
ON Nõ) tNN
XLV
[01761 A suspension of intermediate 32 (0.30.g, 1.0 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (0.35 g, 1.2 mmol), Pd2(dba)3 (60 mg, 0.066 mmol), Xantphos (70 mg, 0.12 mmol) and cesium carbonate (0.70 g, 2.1 mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (40 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/7, 40 mL). After filtration, the title compound was obtained as an off white solid (0.30 g, 59%).
[0177] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.11 (s, 3H), 2.22 (s, 3H), 2.45 (t, J= 4.7 Hz, 4H), 3.02 (t, J= 4.8 Hz, 4H), 6.81 (d, J= 9.1 Hz, 2H), 7.45-7.52 (m, 4H), 7.56 (s, 1H), 7.89 (s, 1H), 8.10-8.16 (m, 2H), 8.51 (s, 1H), 8.70 (s, 1H) MS (ES+):
in/z 510 (M+H)+.
EXAMPLE 76. N-tert-Buty1-3-(2-eh1oro-5-methy1-nvrimidin-4-y1amino)-benzenesulfonamide (Intermediate 33) Ho 411 N'g NH
N
I
CI
[0178] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium calbmlate (2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in Et0Ac and hexanes added until solid precipitated. After filtration, the title compound (1.2 g, 98%) was obtained as a light brown solid. It was Used in the next step without purification. MS (ES+): m/z 355 (M+H)+.
EXAMPLE 77. N-tert-Butyl-345-methy1-2-(4-morpho1in-4-Amethyl-pheny1amino)-= pyrimidin-4-ylamino[-benzenesulfonamide (Compound XLVI1 NH
N N
NN LO
XLVI
[0179] A mixture of intermediate 33 (0.50 g, 1.4 mmol), 4-morpholin-4-ylmethyl-phenylamine (0.35 g, 1.8 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (1.0 g, 3.1 mmol) was suspended in dioxane (25 mL) and heated at reflux under the argon atmosphere for 3 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (50 mL). The combined aqueous layers were extracted with Et0Ac (2 x 50 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.23 g, . 31%).
[0180] IFINMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.13 (s, 3H), 2.28-2.34 (m, 4H), 3.35 (s, 2H), 3.55 (t, .1= 4.8 Hz, 4H), 7.10 (d, J= 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.57 (s, 1H), 7.59 (d, J= 8.5 Hz, 2H), 7.94 (s, 1H), 8.10 (s, 1H), 8.13-8.16 (m, 1H), 8.58 (s, 1H), 8.95 (s, 1H). MS (ES+): /72/z 511 (M+H)+.
EXAMPLE 78. N-tert-Buty1-3-{5-methy1-2-[4-(4-oxy-morpholin-4-ylmethyl)-phenylamino[-pyrimidin-4-ylaminol-benzenesulfonamide (Compound XLVH) Or-NH
NH
N+Th kNN ,-0 XLVII
[0181] A solution of the above-described compound XLVI (30 mg, 0.06 mrnol) and chloroperbenzoic acid (77%, 14 mg, 0.06 mmol) in chloroform (30 mL) was strred at room temperature for 1 hour. The solvent was removed by rotovap and the resulting mixture was purified by silica gel with 20% CH3OH/CHC13 as an eluent to afford the title compound as an off-white solid (15 mg, 48%).
[0182] 1H
NMR (500 MHz, DMSO-d6): 8 1.12 (s, 911), 2.14 (s, 3H), 2.71 (d, J= 10.9 Hz, 214), 3.63 (d, J= 9.9 Hz, 2H), 4.08 (t, J= 11.6 Hz, 2H), 4.28 (s, 2H), 7.38 (d, J= 8.5 Hz, 2H), 7.50 (d, J 5.0 Hz, 2H), 7.61 (s, 111), 7.66 (d, J-= 8.5 Hz, 2H), 7.96 (s, 1H), 8.13 (m, 2H), 8.63 (s, 1H), 9.13 (s, 111). MS (ES+): in/z 527 (M+H)+.
EXAMPLE 79. N-tert-Buty1-345-methyl-244-pyrazol-1-14-phenylamino)-pyrimidin-4-vlaminol-benzenesulfonamide (Compound XLVIII) NH \
8 -õ), NN
XLVIII
[0183] A
mixture of intermediate 33 (0.10 g, 0.28 mrnol) and 4-pyrazol-1-yl-phenylamine (50 mg, 0.31 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken up in water (20 mL) and neutralized with 10% NaOH solution until solid precipitated. The brown solid was filtered and then purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).
[0184] 1HNMR
(500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.15 (s, 3H), 6.49 (t, J= 2.2 Hz, 1H), 7.50-7.55 (m, 2H), 7.58 (s, 1H), 7.62 (d, J= 9.1 Hz, 2H), 7.68 (d, J= 1.3 Hz, 1H), 7.77 (d, J= 9.1 Hz, 2H), 7.96 (s, 1H), 8.11 (s, 1H), 8.13-8.16 (m, 1H), 8.33 (d, J=
2.5 Hz, 1H), 8.64 (s, 1H), 9.17 (s, 1H). MS (ES+): m/z 478 (M+H)+.
EXAMPLE 80. N-tert-Buty1-345-methy1-2-(6-piperazin-1-yl-pyridin-3-ylamino)-pyrimidin-4-ylamino[-benzenesulfonamide (Compound XLDC) HO lel >1\l'g NH
I I
Nr XLIX
[0185] A
mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(5-amino-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.32 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C
for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was dissolved in DCM (5 mL) and 30% TFA/DCM (6 mL) added. The mixture was stirred at room temperature for lh, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2504 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (10 mg, 7%).
[0186] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.11 (s, 3H), 2.83 (t, J=
5.0 Hz, 4H), 3.28-3.33 (in, 4H), 6.73 (d, J= 9.1 Hz, 1H), 7.40-7.49 (in, 2H), 7.57 (s, 1H), 7.86 (dd, J
= 9.1, 2.7 Hz, 1H), 7.88 (s, 1H), 8.10-8.16 (in, 2H), 8.28 (d, J= 2.5 Hz, 1H), 8.53 (s, 1H), 8.72 (s, 1H). MS (ES+): nilz 497 (M+H)+.
EXAMPLE 81. N-tert-Buty1-3-[5-methyl-244-pyrazol-1-ylmethyl-phenylamino)-pyrimidin-4-ylamino1-benzenesulfonamide (Compund L) Ho N I I
NH
N 401 NI:: I \ji N N
[0187] A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-pyrazol-1-ylmethyl-phenylamine (50 mg, 0.29 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C for 15 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (12 mg, 9%).
[0188] 1HNMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.13 (s, 3H), 5.21 (s, 2H), 6.24 (t, J= 1.9 Hz, 1H), 7.08 (d, J= 8.5 Hz, 2H), 7.27-7.50 (m, 3H), 7.56 (s, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.75 (d, J= 2.1 Hz, 1H), 7.94 (s, 1H), 8.14 (d, J= 7.9 Hz, 1H), 8.59 (s, 1H), 9.01 (s, 1H). MS (ES+): nilz 492 (M+H)+.
EXAMPLE 82. 5-Methyl-N2-[3-(piperidine-1-su1fony1)-pheny11-pyrimidine-2,4-diamine (Intermediate 34) N
N
N N
it [0189] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mrnol) and 3-(piperidine- 1-sulfony1)-phenylamine (0.50 g, 2.1 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to ¨9 with 10% NaOH solution. The resulting solution was extracted with Et0Ac (2 x 30 mL) and the organic layer separated.
The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated in vacuo and the crude product (-0.6 g) used in the next step without purification. MS (ES+): m/z 348 (M+H)+.
EXAMPLE 83. N-tert-Buty1-3-{5-methy1-2-[3-(piperidine-1-sulfony1)-phenylaminol-pyrimidin-4-ylaminolt-benzenesulfonamide (Compound LI) HO si=¨N
NH
1.1.1 40 0 NN
LI
[01901 A suspension of intermediate 34 (0.10 g, 0.29 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (84 mg, 0.29 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (20 mg, 12%).
[0191] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 1.30-1.40 (m, 2H), 1.50-1.56 (m, 4H), 2.16 (s, 3H), 2.88 (t, J= 5.3 Hz, 4H), 7.17 (d, J= 7.8 Hz, 1H), 7.43 (t, J= 8.0 Hz, 1H), 7.59-7.60 (m, 2H), 7.58 (s, 1H), 8.13 (s, 1H), 7.16 (dd, J= 7.9, 1.9 Hz, 1H), 8.18-8.22 (m, 1H), 8.67 (s, 1H), 9.37 (s, 1H). MS (ES+): 171/Z 559 (M+H)+.
EXAMPLE 84. N-tert-Buty1-345-methy1-2-14-(4-methyl-piperazin4-ylmethvb-pheny1aminol-pyrimidin-4-y1aminol-benzenesulfonamide (Compound LII) HQ
NH
N N
1\17. N
LII
[0192] A suspension of intetinediate 33 (0.10 g, 0.28 mmol), 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (65 mg, 0.32 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (53 mg, 36%).
[0193] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.13 (s, 3H), 2.15 (s, 3H), 2.20-2.45 (m, 4H), 3.25-3.40 (m, 6H), 7.08 (d, J.= 8.6 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1H), 7.57 (d, J= 8.6 Hz, 2H), 7.94 (s, 1H), 8.09 (s, 1H), 8.13-8.16 (m, 1H), 8.58 (s, 1H), 8.94 (s, 1H). MS (ES+): m/z 524 (M+H)+.
EXAMPLE 85. N-tert-Buty1-3-15-methy1-2-(4-piperazin-1-y1-3-trifluoromethyl-pheny1amino)-pyrimidin-4-y1amino1-benzenesu1fonamide (Compound LIII) HO
N N
LIII
[0194] A
mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-amino-2-trifluoromethyl-pheny1)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.29 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was dissolved in DCM (5 mL) and 50% TFA/DCM (6 mL) added.
The mixture was stirred at room temperature for 2h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and. the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (42 mg, 26%).
[0195] 1H
NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.14 (s, 3H), 2.70-2.75 (m, 4H), 2.80-2.85 (m, 4H), 7.36 (d, J= 8.5 Hz, 2H), 7.45-7.52 (in, 2H), 7.55 (s, 1H), 7.90-8.00 (m, 3H), 8.07 (s, 1H), 8.15 (d, J= 7.6 Hz, 1H), 8.63 (s, 1H), 9.22 (s, 1H) MS
(ES+): m/z 564 (M+H)+.
EXAMPLE 86. 3-{2-14-(4-Acetyl-piperazin-1-0.)-3-trifluoromethyl-phenylamino]-5-methyl-pyrimidin-4-ylaminol-N-tert-butyl-benzenesulfonamide (Compound LIV) H 0 el N
LIV
[0196] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 144-(4-amino-2-trifluoromethyl-pheny1)-piperazin- l-y1]-ethanone (0.1 g, 0.35 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (64 mg, 38%).
[0197] NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.04 (3, H), 2.14 (s, 3H), 2.73 (t, J
= 4.9 Hz, 2H), 2.79 (t, J= 4.7 Hz, 2H), 3.50-3.60 (in, 4H), 7.40 (d, J= 8.7 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1H), 7.90-8.00 (m, 3H), 8.07 (s, 1H), 8.14 (d, J= 7.2 Hz, 1H), 8.64 (s, 1H), 9.26 (s, 1H). MS (ES+): 171/Z 606 (M+H)+.
EXAMPLE 87. 5-Methyl-N2-13-(4-methyl-piperazine-1-sulfonv1)-phenyll-pyrimidine-2,4-diamine (Intermediate 351 nit H2 N N
[0198] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol) and 3-(4-methyl-piperazine-1-sulfony1)-phenylamine (0.50 g, 2.0 mmol) in acetic acid (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 130 C
for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and pH adjusted to ¨9 with 10% NaOH
solution. The resulting solution was extracted with Et0Ac (2 x 30 mL) and the organic layer separated.
The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product (-0.42 g) used in the next step without purification. MS (ES+): m/z 363 (M+H)+.
EXAMPLE 88. N-tert-Buty1-345-methyl-243-(4-methyl-piperazine-1-sulfony1)-phenylaminol-pyrimidin-4-ylarninol-benzenesulfonamide (Compound LV) Ho >N 101 ,A
NH
N-40) N N
LV
[0199] A suspension of intermediate 35 (0.10 g, 0.28 mmol), 3-bromo-N-tert-butyl-benzenesulfonamide (80 mg, 0.27 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue dissolved in minimum amount of Et0Ae and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (10 mg, 6%).
[0200] 1H NMR (500 MHz, DMSO-d6): 5 1.12 (s, 9H), 2.13 (s, 3H), 2.16 (s, 3H), 2.33-2.40 (m, 4H), 2.85-2.94 (m, 4H), 7.18 (d, J= 8.1 Hz, 1H), 7.44 (t, J= 8.0 Hz, 1H), 7.49-7.54 (m, 2H), 7.58 (s, 1H), 8.00-8.03 (m, 2H), 8.13 (s, 1H), 8.15 (dd, J= 8.6, 1.6 Hz, 1H), 8.18-8.23 (m, 1H), 8.66 (s, 1H), 9.38 (s, 1H). MS (ES+): m/z 574 (M+H)+.
EXAMPLE 89. N-tert-Buty1-345-methy1-2-(4-piperazin-1-ylmethyl-phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LVI) Ho N
NH
NN NH
LVI
[0201] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-amino-benzy1)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g, 0.34 mmol), Pd2(dba)3 (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate (0.20g, 0.61 mmol) in dioxane/DMF
(3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C
for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was dissolved in DCM (6 mL) and TFA (3 mL) added. The mixture was stirred at room temperature for lh, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid triturated in hexanes/Et0Ac (10/1, 55 mL). After filtration, the title compound was obtained as a white solid (32 mg, 22%).
[0202] NMR (500 MHz, DMSO-d6): 61.12 (s, 9H), 2.13 (s, 3H), 2.30-2.40 (m, 4H), 2.85 (t, J= 4.7 Hz, 4H), 3.38 (s, 2H), 7.09 (d, J= 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1H), 7.59 (d, J= 8.5 Hz, 2H), 7.94 (s, 1H), 8.10 (s, 1H), 8.13-8.16 (m, 1H), 8.59 (s, 1H), 8.96 (s, 1H). MS (ES+): mtz 510 (M+H)+.
EXAMPLE 90. N-tert-Buty1-3-{5-methy1-2-1-4-(2-pyrrolidin-l-yl-ethoxy)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LVII) H
>Nic);N
NH
N
N N
LVII
[0203] A mixture of intermediate 33 (0.10 g, 0.28 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C for 20 min. After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid dissolved in minimum amount of Et0Ac and hexanes added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).
[0204] IHNMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s, 3H), 2.45-2.55 (m, 4H), 2.76 (t, J= 5.8 Hz, 2H), 3.99 (t, J= 6.0 Hz, 2H), 6.79 (d, J= 9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H).
MS (ES+): nilz 525 (M+H)+.
EXAMPLE 91. 3-15-Methv1-2-[444-methyl-piperazin-1-y1)-phenylamino]-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LVIII) H2N.C?
NH
8 N) kN)N
LVIII
[0205] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-benzenesulfonamide (0.10 g, 0.42 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC.
The fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a grey solid (10 mg, 7%).
[0206] 1H NMR (500 MHz, DMSO-d6): 8 2.10 (s, 3H), 2.22 (s, 3H), 2.44 (t, J=
4.9 Hz, 4H), 3.03 (t, J= 4.9 Hz, 4H), 6.81 (d, J= 9.0 Hz, 2H), 7.34 (s, 2H), 7.45-7.50 (m, 4H), 7.89 (s, 1H), 8.06 (s, 1H), 8.13-8.18 (m, 1H), 8.54 (s, 1H), 8.70 (s, 1H). MS
(ES+): m/z 454 (M+H)+.
EXAMPLE 92. N-Methy1-3-15-methyl-2-[4-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LIX) Ho 1.1 NH
8 ,õ7-LN
I
N
LIX
[0207] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N-methyl-benzenesulfonamide (0.11 g, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and in-adiated with microwave at 160 C
for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of DCM/Et20 (1/5, 30 mL).
After filtration, the title compound was obtained as a light brown solid (65 mg, 42%).
[0208] IHNMR. (500 MHz, DMSO-d6): 5 2.11 (s, 3H), 2.23 (s, 3H), 2.44 (d, J
5.0 Hz, 3H), 2.45-2.50 (m, 4H), 3.03 (t, J= 4.9 Hz, 4H), 6.81 (d, J= 9.1 Hz, 2H), 7.40-7.43 (m, 2H), 7.46 (d, J= 9.1 Hz, 2H), 7.52 (t, J= 8.0 Hz, 1H), 7.89 (s, 1H), 7.94 (t, J=
1.8 Hz, 1H), 8.29 (br d, J= 8.3 Hz, 1H), 8.56 (s, 1H), 8.72 (s, 1H). MS (ES+): m/z 468 (M+H)+.
EXAMPLE 93. N,N-Dimethy1-3-{5-methyl-2-[4-(4-methyl-piperazin-1-y1)-phenylaminol-pyrirnidin-4-ylaminol-benzenesulfonamide (Compound LX) lo= el N
NH
N
LX
[0209] A suspension of intemiediate 32 (0.13 g, 0.43 mmol), 3-bromo-N,N-dimethy1-benzenesulfonamide (0.14 g, 0.53 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.33 g, 1.0 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture ofEt0Ac/hexanes (1/5, 30 mL). After filtration, the title compound was obtained as an off white solid (60 mg, 29%).
[0210] 1H NMR (500 MHz, DMSO-d6): 8 2.17 (s, 3H), 2.23 (s, 3H), 2.44 (d, J=
5.0 Hz, 3H), 2.45-2.50 (m, 4H), 2.63 (s, 6H), 3.03 (t, J= 4.9 Hz, 4H), 6.81 (d, J= 9.1 Hz, 2H), 7.36 (d, J¨ 8.0 Hz, 1H), 7.45 (d, J= 9.1 Hz, 2H), 7.54 (t, J= 8.0 Hz, 1H), 7.84 (t, J= 1.9 Hz, 1H), 7.90 (s, 1H), 8.46 (br d, J= 7.8 Hz, 1H), 8.57 (s, 1H), 8.74 (s, 1H). MS
(ES+): m/z 482 (M+H)+ .
EXAMPLE 94. N-Isopropy1-3-{5-methy1-2-14-(4-methyl-piperazin-1-yI)-phenylamino)-pyrimidin-4-ylamino)-benzenesulfonamide (Compound LXI) NH
ON
tNN
LXI
[0211] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N-isopropyl-benzenesulfonamide (0.11 g, 0.39 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as an off white solid (47 mg, 29%).
[0212] 1H NMR (500 MHz, DMSO-d6): 60.98 (d, J= 6.6 Hz, 6H), 2.11 (s, 3H), 2.24 (s, 3H), 2.45-2.50 (m, 4H), 3.03 (t, J= 4.8 Hz, 4H), 3.20-3.27 (m, 1H), 6.80 (d, J= 9.0 Hz, 2H), 7.40-7.52 (m, 4H), 7.59 (d, J= 7.1 Hz, 1H), 7.89 (s, 1H), 8.21 (br d, J= 7.9 Hz, 1H), 8.53 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 496 (M+H)+.
EXAMPLE 95. Ar4-(3-Methanesulfonv1-4-methyl-pheny1)-5-methyl-N2-14-(4-methyl-piperazin-1-y1)-phenyll-p_yrimidine-2,4-diamine (Compound LXII) y=
NH rThe I
N
LXII
[0213] A suspension of inteimediate 32 (0.10 g, 0.33 mmol), 4-bromo-2-methanesulfonyl-1-methyl-benzene (0.10 g, 0.40 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/5, 30 mL). After filtration, the title compound was obtained as a light brown solid (41 mg, 27%).
[0214] 111 NMR (500 MHz, DMSO-d6): 8 2.09 (s, 3H), 2.22 (s, 3H), 2.45 (t, J= 4.7 Hz, 4H), 2.61 (s, 3H), 3.03 (t, J= 4.9 Hz, 4H), 3.20 (s, 3H), 6.80 (d, J= 9.1 Hz, 2H), 7.35 (d, J=
8.5 Hz, 1H), 7.44 (d, J= 9.0 Hz, 2H), 7.87 (s, 1H), 8.05 (d, J¨ 2.4 Hz, 1H), 8.21 (br d, J-7 .0 Hz, 1H), 8.55 (s, 1H), 8.71 (s, 1H). MS (ES+): nilz 467 (M+H) .
EXAMPLE 96. N-Cyclohexy1-3-{5-methy1-244-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylamino}-benzenesulfonamide (Compound LXIH) r-.Nr (1,`
NH
LJON
tNI*
LXIII
[02151 A suspension of intermediate 32 (0.10 g, 0,33 mmol), 3-bromo-N-cyclohexyl-benzenesulfonamide (0.13 g, 0.41 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as an off white solid (45 mg, 25%).
[02161 1H NMR (500 MHz, DMSO-d6): 6 1.07-1.17 (m, 6H), 1.53-1.63 (m, 4H), 2.11 (s, 3H), 2.22 (s, 3H), 2.45 (t, J= 4.7 Hz, 4H), 2.90-3.00 (in, 1H), 3.02 (t, J=
4.8 Hz, 4H), 6.80 (d, J= 9.1 Hz, 2H), 7.43-7.53 (m, 4H), 7.65 (d, J= 7.3 Hz, 1H), 7.89 (s, 1H), 8.05 (s, 1H), 8.18 (br d, J= 7.7 Hz, 1H), 8.52 (s, 1H), 8.71 (s, 1H). MS (ES+): nilz 536 (M+H)+.
EXAMPLE 97. N,N-Diethy1-3-15-methyl-2-[444-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LXIV) == I.
NH
I
N
LXIV
[02171 A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-N,N-diethyl-benzenesulfonamide (0.12 g, 0.41 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as an off white solid (45 mg, 27%).
[0218] 1H NMR (500 MHz, DMSO-d6): 5 1.06 (t, J= 7.1 Hz, 6H), 2.11 (s, 3H), 2.22 (s, 3H), 2.44 (t, J= 4.7 Hz, 4H), 3.03 (t, J= 4.8 Hz, 4H), 3.16 (q, J= 7.1 Hz, 4H), 6.80 (d, J=
9.1 Hz, 2H), 7.39 (d, J= 8.1 Hz, 1H), 7.45 (d, J= 9.0 Hz, 2H), 7.50 (t, J= 8.1 Hz, 1H), 7.89 (t, J= 1.9 Hz, 1H), 7.89 (s, 1H), 8.39 (br d, J= 7.9 Hz, 1H), 8.53 (s, 1H), 8.74 (s, 1H). MS
(ES+): nilz 510 (M+H)+.
EXAMPLE 98. 5-Methyl-N2-1444-methyl-piperazin-1-y1)-pheny11-/V4-(3-(morpholine-sulfony1)-phenyll-pyrimidine-2,4-diamine (Compound LXV) ,Ii 0 e N l NH
N
N
LXV
[0219] A suspension of inteimediate 32 (0.10 g, 0.33 mmol), 4-(3-bromo-benzenesulfony1)-morpholine (0.12 g, 0.39 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF
(3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC. The fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as a light red solid (90 mg, 52%).
[0220] 1H NMR (500 MHz, DMSO-d6): 5 2.12 (s, 3H), 2.22 (s, 3H), 2.45 (t, J=
4.8 Hz, 4H), 2.89 (t, J= 4.6 Hz, 4H), 3.03 (t, J= 4.8 Hz, 4H), 3.64 (t, J= 4.7 Hz, 4H), 6.81 (d, J=
9.1 Hz, 2H), 7.35 (d, J= 8.1 Hz, 1H), 7.45 (d, J= 9.0 Hz, 2H), 7.56 (t, J= 8.1 Hz, 1H), 7.84 (t, J= 1.9 Hz, 1H), 7.91 (s, 1H), 8.47 (br d, J= 8.4 Hz, 1H), 8.59 (s, 1H), 8.75 (s, 1H). MS
(ES+): m/z 524 (M+H)+.
EXAMPLE 99. 3-{5-Methyl-2-44-(4-methyl-piperazin-1-y1)-phenylamino[-pyrimidin-ylaminol-benzoic acid ethyl ester (Intermediate 36) Et0 NH
I
N
[0221] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-benzoic acid ethyl ester (0.07 mL, 0.44 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 10% Me0H/DCM) to afford the title compound (0.10 g, 68%). MS (ES+): in/z 447 (M+H)+.
EXAMPLE 100. 3-15-Methyl-2-14-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzamide (Compound LXVI) NH N-N
tNN
LXVI
[0222] A mixture of intermediate 36 (0.10 g, 0.22 mmol) in concentrated NH4OH
was sealed in a reaction tube and heated at 50 C for 3 d. The mixture was poured into water (15 mL) and extracted with Et0Ac (2 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2504 and filtered.
The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as a white solid (10 mg, 11%).
[0223] 1H NMR (500 MHz, DMSO-d6): 6 2.10 (s, 3H), 2.22 (s, 3H), 2.40-2.50 (m, 4H), 2.95-3.05 (m, 4H), 6.75 (d, J= 9.1 Hz, 2H), 7.30-7.40 (in, 2H), 7.45 (d, J=
9.1 Hz, 2H), 7.53-7.58 (m, 1H), 7.85 (s, 1H), 7.90 (br s, 2H), 8.03 (s, 1H), 8.37 (s, 1H), 8.71 (s, 1H). MS
(ES+): nilz 418 (M+H)+.
EXAMPLE 101. 2-Methyl-3-{5-methyl-2-14-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-y1aminol-benzoic acid ethyl ester (Compound LXVII1 0 0 Et Nõ N
NNS
LXVII
[0224] A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-2-methyl-benzoic acid ethyl ester (0.10 mL, 0.41 mmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% Me0H and 1% TEA in DCM) to afford the title compound (0.14 g, 92%) as a light brown oil.
[0225] 1H NMR (500 MHz, DMSO-d6): 6 1.32 (t, J= 7.1 Hz, 3H), 2.10 (s, 3H), 2.21 (s, 3H), 2.32 (s, 3H), 2.40-2.45 (m, 4H), 2.94 (t, J= 4.8 Hz, 4H), 4.30 (q, J= 7.1 Hz, 2H), 6.57 (d, J= 9.1 Hz, 2H), 7.25 (d, J= 8.9 Hz, 2H), 7.35 (t, J= 7.8 Hz, 1H), 7.48 (dd, J= 7.9, 1.0 Hz, 1H), 7.70 (dd, J= 7.8, 1.1 Hz, 1H), 7.78 (s, 1H), 8.23 (s, 1H), 8.58 (s, 1H). MS (ES+):
nilz 461 (M+H)+.
EXAMPLE 102. 2-Methy1-3-15-methy1-2-[4-(4-methyl-piperazin-1-y1)-phenylamino]-pyrimidin-4-ylaminol-benzamide (Compound LXVIII) le NH
NN
LXVIII
[0226] To a mixture of the above-described compound LXVII (0.10 g, 0.22 mmol) and formamide (0.05 mL, 1.3 mmol) in DMF (5 mL) at 100 C was added Na0Me (0.10 g, 0.46 mmol) under the argon atmosphere. The mixture was stirred at the same temperature for 2 h and then at room temperature for additional 15 h. The mixture was poured into water (15 mL) and extracted with Et0Ac (2 x 15 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and the residue triturated in a mixture of Et0Ac/hexanes (1/5, 30 mL). After filtration, the title compound was obtained as a white solid (20 mg, 21%).
[0227] NMR (500 MHz, DMSO-d6): 8 2.09 (s, 3H), 2.21 (s, 3H), 2.23 (s, 3H), 2.40-2.45 (m, 4H), 2.97 (t, J= 4.8 Hz, 4H), 6.69 (d, J= 9.1 Hz, 2H), 7.24-7.28 (m, 2H), 7.35 (d, J= 9.0 Hz, 2H), 7.39-7.43 (m, 2H), 7.69 (s, 1H), 7.78 (s, 1H), 8.01 (s, 1H), 8.53 (s, 1H). MS (ES+):
m/z 432 (M+H)+.
EXAMPLE 103. (2-Chloro-5-methyl-pyrimidin-4-y1)-(4-ehloro-3-trifluoromethyl-pheny1)-amine (Intermediate 37) CI si \)k-.
CI
[0228] A mixture of 2-ehloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol), bromo-1-chloro-2-trifluoromethyl-benzene (0.40 mL, 2.7 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.22 mmol) and cesium carbonate (1.5 g, 4.6 mmol) in dioxane/DMF (6/1, 7 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 15 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 50%
Et0Ae/hexanes) to afford the title compound (0.65 g, 96%) as a white solid. MS
(ES+): rth 322 (M+H)+.
EXAMPLE 104. N4-(4-Ch1oro-3-trifluoromethy1-pheny1)-5-methy1-N2-1.4-(piperidin-yloxy)-phenyll-pyrimidine-2,4-diamine (Compound LXIX) CI
akt N NH
LXIX
[0229] A mixture of intermediate 37 (0.10 g, 0.31 mmol) and 4-(4-amino-phenoxy)-piperidine-1-earboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C
for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and neutralized with 10% NaOH solution until solid precipitated. The resulting solid was filtered and purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a white solid (30 mg, 20%).
[0230] 1H
NMR (500 MHz, DMSO-d6): 8 1.69-1.77 (in, 2H), 2.00-2.04 (m, 2H), 2.11 (s, 3H), 2.90-3.00 (in, 2H), 3.10-3.20 (in, 2H), 4.40-4.48 (in, 1H), 6.84 (d, J=
9.0 Hz, 2H), 7.49 (d, J= 9.0 Hz, 2H), 7.58 (d, J= 8.8 Hz, 1H), 7.94 (s, 1H), 8.12 (d, J= 2.6 Hz, 1H), 8.21 (br d, J= 8.2 Hz, 1H), 8.64 (s, 1H), 8.93 (s, 1H). MS (ES+): m/z 478 (M+H)+.
EXAMPLE 105. 5-Methyl-N2-14-(2-pyrrolidin-1-yl-ethoxy)-phenyll-pyrimidine-2,4-diamine (Intermediate 38) ' NN
[0231] A
mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (1.1 g, 5.3 mmol) in acetic acid (8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C for 15 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH ¨10.
The resulting aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a grey solid (0.80 g, 73%). It was used in the next step without purification. MS (ES+): m/z 314 (M+H)+.
EXAMPLE 106. 3-45-Methy1-2-14-(2-pyrrolidin-1-yl-ethoxy)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound LXX), H2N,9 N
LXX
[0232] A mixture of intermediate 38 (0.10 g, 0.32 mmol), 3-bromo-benzenesulfonamide (0.10 g, 0.42 rnmol), Pd2(dba)3 (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 25 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered and the filtered solid washed with DCM. The filtrate was concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and solid triturated in a mixture of Et0Ac/hexanes (1/10, 33 mL). After filtration, the title compound was obtained as a white solid (11 mg, 7%).
[0233] 111 NMR (500 MHz, DMSO-d6): 8 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.49-2.52 (m, 4H), 2.75-2.80 (m, 2H), 4.00 (t, J = 5.9 Hz, 2H), 6.80 (d, J= 9.0 Hz, 2H), 7.34 (s, 2H), 7.45-7.50 (m, 2H), 7.52 (d, J 9.0 Hz, 2H), 7.90 (s, 1H), 8.05 (s, 1H), 8.10-8.15 (m, 1H), 8.57 (s, 1H), 8.77 (s, 1H). MS (ES+): inlz 469 (M+H)+.
EXAMPLE 107. 5-Methyl-N2-(4-morpholin-4-vImethyl-nhenv1)-pyrimidine-2,4-diamine (Intermediate 39) N.)N
[0234] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.40 g, 2.8 mmol) and 4-morpholin-4-ylmethyl-phenylamine (0.60 g, 3.1 mmol) in acetic acid (15 mL) was heated at 70 C for 17 h. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH ¨10.
The resulting aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to afford the title compound as a brown syrup (0.70 g, 83%). It was used in the next step without purification. MS (ES+): nilz 300 (M+H)+
EXAMPLE 108 M-(1H-Indo1-4-y1)-5-methyl-N2-(4-morpholin-4-ylmethyl-pheny1)-pyrimidine-2,4-diamine (Compound UM) HN
411) NH
NiLN c0 "XXI
[0235] A mixture of intetmediate 39 (0.40 g, 1.3 mmol), 4-bromo-1-triisopropylsilanyl-1H-indole (0.50 g, 1.4 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (0.90 g, 2.8 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes to Et0Ac) to afford the TIPS protected precursor as a yellow oil.
[0236] To the above TIPS protected precursor (50 mg, 0.088 mmol) in THF (5 mL) was added TBAF (0.5 mL, 1M in THF). The mixture was stirred at room temperature for 1 h and then poured into water (20 mL). The aqueous layer was extracted with Et0Ac (2 x 20 mL) and the combined organic layers washed With brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and solid dissolved in minimum amount of Et0Ac and then hexanes added until solid precipitated.
After filtration, the title compound was obtained as a light brown solid (6 mg, 1% overall yield).
[0237] 1H NMR (500 MHz, DMSO-d6): 62.17 (s, 3H), 2.25-2.30 (m, 4H), 3.29 (s, 2H), 3.54 (t, J= 4.5 Hz, 4H), 6.40 (t, J= 2.2 Hz, 1H), 6.89 (d, J= 8.5 Hz, 2H), 7.09 (t, J= 7.8 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.27 (t, J= 2.8 Hz, 1H), 7.30 (d, J= 7.5 Hz, 1H), 7.43 (d, Jr 8.5 Hz, 2H), 7.85 (s, 1H), 8.14 (s, 1H), 8.77 (s, 1H), 11.10 (s, 1H). MS
(ES+): nilz 415 (M+H)+ .
EXAMPLE 109. 4-1-4-(4-Amino-5-methyl-pyrimidin-2-ylamino)-benzyl[-piperazine-1-= carboxylic acid tert-butyl ester (Intermediate 40) N`
N
N N
40 Boc [0238] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.35 g, 2.4 mmol) and 4-(4-amino-benzy1)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 2.8 mmol) in acetic acid (20 inL) was heated at 70 C for 1 d. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10%
NaOH
solution until pH ¨10. The resulting aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the title compound used in the next step without purification. MS (ES+): nz/z 399 (M+H) .
EXAMPLE 110. 10-(1H-Indo1-4-y1)-5-methyl-N2-(4-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine (Compound LXXII) HN \
N N') N*N NH
DOCII
[0239] A mixture of intermediate 40 (0.78 g, 2.0 mmol), 4-bromo-1 -triisopropylsilanyl-1H-indole (0.70 g, 2.0 mmol), Pd2(dba)3 (0.15 g, 0.16 mmol), Xantphos (0.19 g, 0.32 mmol) and cesium carbonate (1.3 g, 4.0 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 4.5 h. The reaction mixture was cooled to room temperature, filtered and the filtered solid was with DCM (30 mL). The filtrate was concentrated and the residue purified by flash chromatography on silica gel (hexanes to 30%
Et0Ac/hexanes) to afford the TIPS protected precursor.
[0240] To the above TIPS protected precursor (0.10 g, 0.15 mmol) in DCM (8 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 h and then concentrated. The residue was purified by HPLC and the corrected fractions combined and poured into saturated NaHCO3 solution (30 mL). The aqueous layer was extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and solid triturated in a mixture of Et0Ac/hexanes (1/5, 30 mL). After filtrationõ the title compound was obtained as a white solid (25 mg, 3% overall yield).
[0241] 1H NMR (500 MHz, DMSO-d6): 8 2.17 (s, 3H), 2.20-2.30 (m, 4H), 2.73 (t, J= 4.6 Hz, 4H), 3.28 (s, 2H), 6.41 (t, J= 2.2 Hz, 1H), 6.89 (d, J= 8.5 Hz, 2H), 7.09 (t, J= 7.8 Hz, 1H), 7.24 (d, J= 8.3 Hz, 1H), 7.27 (t, J= 2.8 Hz, 1H), 7.31 (d, J= 7.5 Hz, 1H), 7.44 (d, J=
8.5 Hz, 2H), 7.85 (s, 1H), 8.13 (s, 1H), 8.77 (s, 1H), 11.10 (s, 1H) MS (ES+): 7n/z 414 (M+H)+, EXAMPLE 111. 5-Methyl-N4-(7-methy1-1H-indo1-4-y1)-N2-(4-(4-methylpiperazin-1-y1)phenyl) pyrimidine-2,4-diamine (Compound LXXIII) NH
H N
.1 N 401 N
N
LXXIII
[0242] A mixture of intermediate 32 (674 mg, 2.25 mmol), 4-bromo-7-methyl-1H-indole (522 mg, 2.48 mmol), Pd2(dba)3 (182 mg, 0.2 mmol), Xantphos (360 mg, 0.6 mmol) and cesium carbonate (2.6 g, 8 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (136 mg of HC1 salt, 13%) as a white solid.
[0243] 1H NMR (500 MHz, DMSO-d6): 8 2.21 (s, 3H), 2.55 (s, 3H), 2.80 (d, J=
4.6 Hz, 3H), 3.00-3.05 (m, 2H), 3.10-3.16 (m, 2H), 3.45-3.48 (in, 2H), 3.64-3.66 (in, 2H), 6.33-6.34 (m, 1H), 6.63 (br, 2H), 6.92-6.97 (in, 4H), 7.35 (t, J= 2.7 Hz, 1H), 7.83 (s, 1H), 10.04 (s, 1H), 10.24 (s, 1H), 11.08 (br s, 1H), 11.34 (s, 1H), 12.12 (br s, 1H). MS
(ES+): m/z 428 (M+H)+.
EXAMPLE 112. N4-(7-Chloro-11/-indo1-4-y1)-5-methyl-N2-(4-(4-methylpiperazin-1-yl)phenyl) pyrimidine-2,4-diamine (Compound LXXIV1 / NH
Cl HN
N
DOCIV
[0244] A mixture of intemiediate 32 (298 mg, 1.0 mmol), 4-bromo-7-chloro-1H-indole (231 mg, 1.04 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (251 mg of HC1 salt, 51%) as a white solid.
[0245] 1H NMR (500 MHz, DMSO-d6): 8 2.21 (s, 3H), 2.80 (d, J= 4.6 Hz, 3H), 3.01-3.05 (m, 2H), 3.08-3.13 (m, 2H), 3.46-3.48 (m, 2H), 3.65-3.67 (m, 2H), 6.46-6.47 (m, 1H), 6.64 (br s, 1H), 6.93 (d, J= 8.9 Hz, 2H), 7.05 (d, J= 8.1 Hz, 2H), 7.25 (d, J= 8.0 Hz, 2H), 7.43-7.44 (m, 1H), 7.87 (s, 1H), 10.13 (s, 1H), 10.27 (s, 1H), 11.00 (br s, 1H), 11.70 (s, 1H), 12.23 (br s, H). MS (ES+): m/z 448 (M+H)+.
EXAMPLE 113. N2-(4-(2-(Pyrrolidin-1-ybethoxy)pheny11-5-methyl-N4-(7-methyl-1H-indol-4-y1) pyrimidine-2,4-diamine (Compound LXXV1 /NH
HN
0,No DON
[0246] A mixture of intermediate 38 (410 mg, 1.3 mmol), 4-bromo-7-methyl-1H-indole (275 mg, 1.3 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo.
The residue was purified by HPLC to afford the title compound (92 mg of HC1 salt, 15%) as a white solid.
[0247] 1H NMR (500 MHz, DMSO-d6): 6 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21 (s, 3H), 2.55 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.54 (m, 4H), 4.26 (t, J= 4.9 Hz, 2H), 6.33-6.34 (m, 1H), 6.61 (br d, 2H), 6.93-6.95 (m, 2H), 7.03 (d, J= 8.9 Hz, 2H), 7.34 (t, J= 2.8 Hz, 1H), 7.85 (s, 1H), 10.07 (s, 1H), 10.33 (s, 1H), 10.91 (br s, 1H), 11.34 (s, 1H), 12.15 (br s, H). MS
(ES+): m/z 443 (M+H)+.
EXAMPLE 114. N2-(4-(2-(Pyrrolidin-1-ybethoxy)pheny1)-5-methyl-N447-ehloro-1H-indol-4-y1) pyrimidine-2,4-diamine (Compound LXXVI) NH
ei CI
HN
()NOI I
NN
LLXVI
[0248] A mixture of intefinediate 38 (270 mg, 0.86 mmol), 4-bromo-7-chloro-1H-indole (198 mg, 0.86 mmol), Pd2(dba)3 (72 mg, 0.08 mmol), Xantphos (140 mg, 0.24 mmol) and cesium carbonate (1.3 g, 4 nu-nol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue Was purified by HPLC to afford the title compound (33 mg of HC1 salt, 8%) as a white solid.
[0249] 1H NMR (500 MHz, DMSO-d6): 8 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.22 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.54 (in, 4H), 4.27 (t, J= 4.9 Hz, 2H), 6.46-6.47 (m, 1H), 6.63 (br d, 2H), 6.95 (d, J= 8.2 Hz, 2H), 7.06 (d, J= 8.0 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.43 (t, J= 2.8 Hz, 1H), 7.90 (s, 1H), 10.13 (s, 1H), 10.40 (s, 1H), 10.94 (br s, 1H), 11.70 (s, 1H), 12.33 (br s, H). MS (ES+): m/z 463 (M+H)+.
EXAMPLE 115. N2-(4-(2-(Pyrrolidin-1-yflethoxy)pheny1)-5-methyl-/V4-(7-fluoro-indol-4-y1) pyrimidine-2,4-diamine (Compound LXXVII) NH
F
H N
.t ONo N N
UOCVII
[0250] A mixture of intermediate 38 (413 mg, 1.3 mmol), 4-bromo-7-fluoro-1H-indole (310 mg, 1.45 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (10 mg of HC1 salt, 1.5%) as a brown solid.
[0251] 1H NMR (500 MHz, DMSO-d6): 8 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.56 (m, 4H), 4.26 (t, J= 4.9 Hz, 2H), 6.42-6.43 (m, 1H), 6.63 (br d, 2H), 6.95-7.04 (m, 3H), 7.35 (d, J= 8.9 Hz, 1H), 7.42 (t, J= 2.8 Hz, 1H), 7.89 (s, 1H), 10.08 (s, 1H), 10.41 (s, 1H), 10.90 (br s, 1H), 11.85 (s, 1H), 12.33 (br s, H). MS (ES+): m/z 447 (M+H)+.
EXAMPLE 116. N4-(3-tert-Butylpheny1)-5-methyl-N244-(4-methylpiperazin-1-14)Phenvbffrimidine-2,4-diamine (Compound UOCVIII) HN
NN) N
=N
LXXVIII
[0252] A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-tert-buty1-3-bromobenzene (256 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo.
The residue was purified by HPLC to afford the title compound (27 mg of HC1 salt, 6%) as a white solid.
[0253] 1H NMR (500 MHz, DMSO-d6): 5 1.25 (s, 9H), 2.16 (s, 3H), 2.80 (d, J=
4.6 Hz, 3H), 3.04-3.16 (m, 4H), 3.47-3.49 (m, 211), 3.65-3.67 (m, 211), 6.90 (d, J= 8.9 Hz, 2H), 7.26 (d, J
9.0 Hz, 2H), 7.28-7.35 (m, 2H), 7.45 (t, J= 1.8 Hz, 1H), 7.50 (d, J= 7.8 Hz, 1H), 7.86 (s, 111), 9.70 (s, 1H), 10.37 (s, 1H), 11.01 (br s, 111), 12.34 (br s, H). MS
(ES+): nilz 431.
(M+H)+.
EXAMPLE 117. N-(3-tert-ButylphenyI)-2-ehloro-5-methylpyrimidin-4-amine (Intermediate 41) 1.1 HN
I
CI
[0254] A mixture of 2-chloro-5-methylpyrimidin-4-amine (670 mg, 4.7 mmol), 1-tert-butyl-3-bromobenzene (1.5 g, 7 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), Xantphos (695 mg, 1.2 mmol) and cesium carbonate (6.2 g, 19 mmol) was suspended in dioxane (150 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacua The residue was dissolved in Et0Ac (10 mL) and added hexanes (100 mL). The solid was collected by filtration and washed with hexanes to afford the crude title compound (1.2 g, 99%) as a yellow solid.
EXAMPLE 118. N4-(3-tert-Butylpheny1)-5-methyl-N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (Compound LXXIX) HN
\) 0 11 ei --CNH
1\17 N
LXXIX
[0255] A mixture of intermediate 41 (740 mg, 2.68 mmol) and tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (500 mg, 1.71 mmol) was suspended in acetic acid (10 mL) and heated at 100 C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (276 mg of HC1 salt, 35%) as a yellow solid.
[0256] 1H NMR (500 MHz, DMSO-d6): 8 1.22 (s, 9H), 1.77-1.81 (m, 2H), 2.03-2.07 (m, 2H), 2.14 (s, 3H), 3.00-3.04 (m, 2H), 3.18 (br s, 2H), 4.56-4.57 (m, 1H), 6.86 (d, J= 8.9 Hz, 2H), 7.26-7.31 (m, 4H), 7.40 (s, 1H), 7.44 (d, J= 7.5 Hz, 1H), 7.84 (s, 1H), 8.93 (br s, 1H), 8.99 (br s, 1H), 9.67 (s, 1H), 10.31 (s, 1H). MS (ES+): nz/z 432 (M+H)+.
EXAMPLE 119. tert-Butyl 444-(4-amino-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-carboxylate (Intermediate 42) o Iei --CNBoc N
[0257] A mixture of 2-chloro-5-methylpyrimidin-4-amine (540 mg, 3.7 mmol), tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (1.1 g, 3.7 mmol) was suspended in acetic acid (20 mL) and heated at 70 C for 1 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 nit) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacua to afford the title compound (1.4 g, 95%) as a yellow solid.
EXAMPLE 120. /V4-(1H-Indazol-4-y1)-5-methyl-N244-(piperidin-4-y1oxy)pheny1)pyrimidine-24-diamine (Compound LXXX) N-NH
HN
= I O-CNH
LXXX
[0258] A mixture of intermediate 42 (480 mg, 1.2 mmol), 4-bromo-1H-indazole (236 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol). was suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo.
The residue was purified by HPLC to afford the title compound (4 mg of HC1 salt, 1.2%) as a yellow solid.
[0259] 1H NMR (500 MHz, DMSO-d6): 6 1.75-1.80 (m, 2H), 2.02-2.07 (m, 2H), 2.24 (s, 3H), 3.05-3.09 (m, 2H), 3.17-3.21 (m, 2H), 4.52 (br s, 1H), 6.63 (d, J= 8.6 Hz, 2H), 7.01 (d, J= 8.6 Hz, 2H), 7.14 (d, J= 7.3 Hz, 2H), 7.38-7.44 (m, 2H), 7.62 (d, J= 8.9 Hz, 2H), 7.92 (s, 1H), 8.02 (s, 1H), 9.00 (br s, 1H), 9.04 (br s, 1H), 10.20 (s, 1H), 10.33 (s, 1H). MS (ES+):
nz/z 416 (M+H)+.
EXAMPLE 121. 4-{3-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-71amino -benz 1 - 1 ester Intermediate 43 CI ip \/
N 410 ri\I 0 N
[0260] A mixture of intermediate 31 (0.092 g, 0.33 mmol), 4-(3-amino-benzy1)-piperazine-1-carboxylic acid tert-butyl ester (0.11 g, 0.39 mmol), Pd2(dba)3 (0.03 g, 0.033 mmol), Xantphos (0.038 g, 0.065 mmol) and cesium carbonate (0.32 g, 0.98 mmol) was suspended in dioxane (5 mL) and microwaved at 160 C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.075 g, 43%) as a brown solid.
EXAMPLE 122. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(3-piperazin-l-Vimethyl-pheny1)-pvrimidine-2,4-diamMe (Compound LXXXI) CI lp NH
NN
N
NH
LXXXI
[0261] A solution of intermediate 43 (0.075 g, 0.14 mmol) in DCM (8 mL) was treated with TFA (2 mL). After 2 h of stirring, solvents were removed and resulting residue was triturated with diethyl ether resulting in white hygroscopic powder (0.05 g, 82%).
[0262] IFT NMR (500 MHz, DMSO-d6): 8 2.17 (s, 3H), 2.89 (br s, 4H), 3.2 (br s, 4H), 3.68 (s, 4H), 3.82 (br s, 3H), 7.16-7.19 (m, 2H), 7.28 (t, J= 7.9 Hz, 1H), 7.33 (d, J= 2.3 Hz, 1H), 7.39 (s, 1H), 7.43 (d, J= 8.5 Hz, 1H), 7.49 (d, 8.6 Hz, 1H), 7.98 (s, 1H), 8.8 (br s, 2H), 9.78 (br s, 1H), 10.57 (br s, 1H). MS (ES+): m/z 439 (M+H)+.
EXAMPLE 123. /V4-(4-Chlor0-3-methoxy-pheny1)-5-methyl-N244-(piperidin-4-yloxY)-pheny1]-pyrimidine-2,4-diamineiCompound LXXXII) Cl (3 N N
LXXXII
[0263] A mixture of intermediate 31 (0.66 g, 2.3 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.88 mg, 3.0 mmol) in acetic acid (15 mL) was microwaved at 160 C for 15 min. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and the mixture was neutralized with 10% NaOH solution until solid precipitated.
Filtration followed by column chromatography yielded the title compound as beige solids (0.51 g, 50%).
[0264] 1H NMR (500 MHz, DMSO-d6): 8 1.37-1.44 (m, 2H), 1.86-1.89 (m, 2H), 2.09 (s, 3H), 2.50-2.56 (m, 2H), 2.91-2.95 (m, 2H), 3.16 (s, 3H), 3.32 (br s, 3H), 3.72 (s, 3H), 4.09 (br s, 1H), 4.21-4.26 (m, 1H), 6.77 (d, J= 9 Hz, 2H), 7.27 (d, J = 8.5 Hz, 1H), 7.40-7.42 (in, 1H), 7.46-7.49 (m, 3H), 7.87 (s, 1H), 8.31 (s, 1H), 8.78 (s, 1H). MS (ES+):
in/z 440 (M+H)+.
EXAMPLE 124. 4-{34444-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-=
ylaminol-phenyll-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 44) Cl le NH
H NO
N N
[0265] A mixture of inteimediate 31 (0.13 g, 0.46 mmol) and 4-(3-amino-pheny1)-piperazine-l-carboxylic acid tert-butyl ester (0.19 mg, 0.68 mmol) in acetic acid (8 mL) was heated at 80 C for 15 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken up in water (20 mL) and the mixture was neutralized with 10% NaOH solution. This was then extracted with ethyl acetate, washed with brine and evaporated to oily residue. Column chromatography yielded =
the title compound as white solids (0.12 g, 48%).
EXAMPLE 125. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(3-piperazin-1-y1-pheny1)-pyrimidine-2,4-diamine (Compound LXXXIII1 CI op N
N N NLXXXIII
NH
[0266] A solution of intermediate 44 (0.11 g, 0.21 mmol) in DCM (8 mL) was treated with TFA (1 mL). After 3 h of stirring, solvents were removed and resulting residue was taken up in ethyl acetate and washed with 10% sodium bicarbonate solution.
Organic phase then dried over sodium sulfate, filtered and evaporated to white powder. This was diluted with DCM (5 mL) and treated with 4M HC1 in dioxane (0.5 mL). Solvents were imediately removed affording HCL salt of title compound as white solids (0.06 g, 67%).
[0267] 1H NMR (500 MHz, DMSO-d6): 8 2.18 (s, 3H), 3.12 (hr s, 4H), 3.22 (hr s, 4H), 3.65 (s, 3H), 6.80 (d, J= 8.1 Hz, 1H), 6.95 (s, 2H), 7.14 (t, J= 8.2 Hz, 1H), 7.23 (d, J= 7.0 Hz, 1H), 7.37-7.40 (m, 2H), 7.95 (s, 1H), 9.33 (hr s,-2H), 9.88 (s; 1H), 10.62 (s, 1H). MS
(ES+): m/z 425 (M+H)+.
EXAMPLE 126. 244-(3-Bromo-pheny1)-piperidin-1-01-ethanol (Intermediate 45) Br N OH
[0268] 4-(3-Bromo-phenyl)-piperidine (1.2 g, 4.8 mmol) and 2-bromoethanol (0.72 mL, 10 mmol) were diluted with DMF (20 mL) and treated with potassium carbonate (2.7 g, 20 mmol). These were stirred at ambient temperature for 18 then poured onto water and extracted with ethyl acetate. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil (0.6 g, 44%).
EXAMPLE 127. 2-14-(3-{5-Methy1-2-f4-(4-methy1-piperazin-1-y1)-pheny1amino1-PYrimidin-4-y1aminol-phenv1)-niperidin-1-1711-ethano1iCompound LXV(IVI
NH
HO N') -N N
LXXXIV
[02691 A mixture of intermediate 32(0.11 g, 0.38 mmol), intermediate 45 (0.21 g, 0.75 mmol), Pd2(dba)3 (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) was suspended in dioxane (10 mL) and microwaved at 160 C
for 15 min. The reaction mixture was cooled to room temperature and centrifuged down.
The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.075 g, 43%) as a purple solid (0.02 g, 11%).
[02701 IH NMR (500 MHz, DMSO-d6): 5 1.60-1.67 (m, 2H), 1.73 (d, J= 11.3 Hz, 2H), 2.02-2.07 (m, 2H), 2.08 (s, 3H), 2.21 (s, 3H), 2.39-2.45 (m, 7H), 2.95 (d, J=
11.4 Hz, 2H), 3.00 (t, J= 4.66 Hz, 4H), 3.50 (t, J= 6.44 Hz, 2H), 6.76 (d, J= 9 Hz, 2H), 6.92 (d, J 8.5 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 7.45-7.49 (m, 3.H), 7.66 (d, J= 7.7 Hz, 1H), 7.82 (s, 1H), 8.09 (s, 1H), 8.67 (s, 1H). MS (ES+): nilz 502 (M+H) .
EXAMPLE 128. 443-Bromo-benzenesulfonylamino)-piperidine-1-carboxylic acid tent-butyl ester (Intermediate 46) Br S, [0271] 3-Bromo-benzenesulfonyl chloride (2.2 g, 8.7 mmol) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2 g, 10 mmol) were combined and diluted with DCM (50 mL) and TEA (3.6 mL, 26 mmol). After 16 h, reaction was poured into separatory funnel and washed with water. Organic phase was then washed with brine, dried over sodium sulfate, filtered and evaporated to clear oil which solidified upon standing (3.6 g, 98%).
EXAMPLE 129. 4-(3-{5-Methy1-244-(4-methyl-piperazin-1-y1)-phenylarninol-pyrimidin-4-y1aminol-benzenesu1fony1amino)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 47) NH, N
NH_ N N
[0272] A mixture of intermediate 32 (0.15 g, 0.518 mmol), intermediate 46 (0.28 g, 0.67 mmol), Pd2(dba)3 (0.024 g, 0.026 mmol), Xantphos (0.03 g, 0.052 mmol) and cesium carbonate (0.34 g, 1 mmol) was suspended in dioxane (10 mL) and microwaved at 160 C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted onto ice. Resulting precipitate dried and carried on directly for deprotection step (0.2 g).
EXAMPLE 130. 345-Methy1-244-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-N-piperidin-4-yl-benzenesulfonamide (Compound LXXXV) H
HNal\L;S\ NH
0/ \O =,cLN N) N N
LXXXV
[0273] Intermediate 47 (0.2 g, 0.32 mmol) was diluted with DCM (10 mL) and treated with TFA (0.3 mL). After 3 h, reaction solvents removed and resulting residue was purified by HPLC (0.01g, 6%).
[0274] 1E1 NMR. (500 MHz, DMSO-d6): 8 1.30-1.35 (m, 2H), 1.56-1.58 (m, 2H), 1.98 (s, 2H), 2.11 (s, 3H), 2.21 (s, 3H), 2.43-2.45 (m, 4H), 2.84-2.87 (m, 2H), 3.02 (t, J= 4.6 Hz, 2H), 6.80 (d, J= 9 Hz, 2H), 7.45-7.51 (m, 4H), 7.78 (br s, 1H), 7.88 (s, 1H), 8.05 (s, 1H), 8.20 (d, J= 7.6 Hz, 1H), 8.53 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 537 (M+H)+.
EXAMPLE 131. N444-(Trifluoromethyl)-3-methylpheny1)-5-methyl-N2-(444-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine hydrochloride (Compound LXXXVI) ,3, NH
I
'f\r N
DOCXVI
[0275] A suspension of intermediate 32 (0.12 g, 0.40 mmol), 1-bromo-3-(trifluoromethyl)-2-methylbenzene (0.14 g, 0.59 mmol), Pd2(dba)3 (37 mg, 0.04 mxnol), Xantphos (47 mg, 0.08 mmol) and cesium carbonate (0.39 g, 1.20 rnmol) in dioxane (20 mL) was degassed with argon for 2 mm then refluxed in a sealed tube for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH3OH/CHC13 as an eluent to afford the title compound as a white solid.
The white was dissolved in CHC13 (30 mL) and titrated with 2 M HC1 in dioxane to pH 1.
The solvent was removed by rotovap and the solid was recrystalized from acetone (25 mg, 13%).
[0276] 1H NMR (500 MHz, DMSO-d6): 62.20 (s, 3H), 2.26 (s, 3H), 2.77 (d, J=
4.5 Hz, 3H), 3.00-3.20 (m, 4H), 3.45 (d, J= 11.6 Hz, 2H), 3.63 (d, J= 12.2 Hz, 2H), 6.71 (d, J= 8.1 Hz, 2H), 7.05 (d, J= 9.0 Hz, 2H), 7.55 (t, J= 7.9 Hz, 1H), 7.63 (d, J= 7.8 Hz, 1H), 7.77 (d, J
= 7.77 Hz, 1H), 7.94 (s, 1H), 10.13 (s, 1H), 10.60 (s, 1H), 11.28 (s, 1H). MS
(ES+): nilz 457 (M+H)+.
EXAMPLE 132. 5-Methyl-N2,-(4-(4-methylpiperazin-1-y1)pheny1)-/V4-(3-(methylsulfonyl)pheny1)-pyrimidine-2,4-diamine (Compound LXXXVII) NH
N
LXXXVII
[0277] A suspension of intermediate 32 (0.13 g, 0.44 mmol), 1-bromo-3-(methylsulfonyl)benzene (0.24 g, 1.0 mmol), Pd2(dba)3 (40 mg, 0.04 mmol), Xantphos (50 mg, 0.08 mrnol) and cesium carbonate (0.43 g, 1.32 mmol) in dioxane (50 mL) was degassed with argon for 2 min then relaxed for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 30% CH3OH/CHC13 as an eluent to afford the title compound as pale yellow solid (35 mg, 15%).
[0278] 1H NMR (500 MHz, DMSO-d6): 62.11 (s, 3H), 2.23 (s, 3H), 2.46 (hr s, 4H), 3.03 (t, J= 4.4 Hz, 4H), 3.19 (s, 3H), 6.81 (d, J= 9.0 Hz, 2H), 7.45 (d, J= 8.9 Hz, 2H), 7.5-7.6 (m, 2H), 7.91 (s, 1H), 8.05 (s, 1H), 8.36 (d, J= 6.7 Hz, 1H), 8.60 (s, 1H), 8.77 (s, 1H). MS
(ES+): in/z 453 (M+H)+.
EXAMPLE 133. 1-Bromo-3-(propylsulfonvflbenzene (Intermediate 48) Br [0279] To a solution of 3-bromobenzenethiol (0.50 g, 2.6 mmol) in dioxane (50 mL) was added 1-iodopropane (1.1 g, 6.5 mmol) and cesium carbonate (2.2 g, 6.8 mmol) was stirred at reflux until all 3-bromobenzenethiol reacted. The reaction was quenched with saturated NaHCO3 solution (25 mL) and the mixture extracted with CHC13 (60 mL). The product in the CHC13 was refluxed with mCPBA (2.9 g, 13 mmol) until all starting reacted.
The organic layer was washed with 2M NaOH to remove the excess of mCPBA, dried over Na2SO4 and filtered. The filtrate was concentrated and the crude product was purified with silica gel column with 1:1 hexanes/CHC13 as an eluent to yield colorless oil (0.30 g, 43%
in 2-steps).
[0280] 1HNMR (500 MHz, DMSO-d6): 0.92 (t, J= 7.4 Hz, 3H), 1.52-1.60 (m, 2H), 3.35-3.38 (m, 2H), 7.63 (t, J= 8.0 Hz, 1H), 7.88-7.91 (m, 1H), 7.95-7.98 (m, 1H), 8.04 (t, J 1.8 Hz, 1H).
EXAMPLE 134. 5-Methyl-N244-(4-methylpiperazin-1-yl)pheny1)-/V4-(3-(propylsulfonyl)pheny1)-pyrimidine-2,4-diamine hydrochloride (Compound LXXXVIH) N
NH
0 N õ1 N
LXXXVIII
[0281] A suspension of intermediate 32 (0.25 g, 0.84 mmol), intermediate 48 (0.26 g, 1 mmol), Pd2(dba)3 (8 mg, 0.01 mmol), Xantphos (16 mg, 0.03 mmol) and cesium carbonate (0.82 g, 2.52 mmol) in dioxane (50 mL) was degassed with argon for 2 mm then refluxed for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH3OH/CHC13 as an eluent to afford the title compound as a white solid. The white was dissolved in CHC13 (30 mL) and titrated with 2 M HC1 in dioxane to pH 1. The solvent was removed by rotovap and the solid was recrystalized from methanol (65 mg, 15%).
[0282] NMR (500 MHz, DMSO-d6): 0.90 (t, J= 7.4 Hz, 3H), 1.50-1.60(m, 2H),2.18 (s, 3H), 2.81 (s, 3H), 3.00-3.13 (m, 4H), 3.27 (t, J= 7.7 Hz, 2H), 3.48 (d, J=
10.9 Hz, 2H), 3.75 (d, J= 11.4 Hz, 2H), 6.95 (d, J= 8.8 Hz, 2H), 7.27 (d, J= 8.9 Hz, 2H), 7.64 (t, J= 8.0 Hz, 1H), 7.73 (d, J= 7.8 Hz, 1H), 7.93 (s, 1H), 8.00 (s, 1H), 8.07 (s, 1H), 9.92 (s, 1H), 10.36 (s, 1H), 10.99 (s, 1H). MS (ES+): nilz 481 (M+H)+.
EXAMPLE 135. 3-(Morpholinomethyl)benzenamine (Intermediate 49) [0283] Zinc chloride (0.1 g, 0.73 mmol) was added to the solution of 3-nitrobenzaldehyde ( 5.9 g, 39.02 mmol), morpholine (3.4 g, 39.02 mmol), sodium cyanoborohydride (2.7 g, 43 mmol) in methanol (50 mL) at room temperature. The solution was heated to reflux for 1 hour. After cooling down , the reaction was quenched by water ( 2 mL) and the methanol was removed by rotovap. The crude product was dissolved in 2M NaOH (50 mL) and extracted by CHC13, dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum.
[0284] The above crude product in methanol (200mL) was reduced by Raney Ni and hydrazine at room temperature. The reaction was monitored by TLC in ethyl acetate. After all starting material reacted, the methanol was removed by rotovap. The crude was purified by silica gel with ethyl acetate as an eluent to yield a white solid (1.5 g, 50% in 2-steps).
[0285] 1H NMR (500 MHz, DMSO-d6): 2.31 (s, 4H), 3.28 (s, 2H), 3.56 (t, J=
4.6 Hz, 4H), 4.97 (s, 2H), 6.40-6.45 (m, 2H), 6.53 (t, J= 1.8 Hz, 1H), 6.93 (t, J= 7.7 Hz, 1H).
EXAMPLE 136 5-Methyl-N2-(3-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine (Intermediate 50) N
N)N N) [0286] A mixture of 2-chloro-5-methylpyrimidin-4-amine (0.17 g, 1.17 mmol) and interrnediate 49 (0.25 g, 1.30 mmol) was suspended in acetic acid (10 mL) and heated at 100 C for 2 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-8.
The resulting solution was extracted with CHC13 (100 mL) and the organic layer separated.
The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by silica gel column with 10 %
CH3OH/Et0Ac as an eluent to afford the title compound as oil (0.15g, 43%).
[0287] 1H NMR (500 MHz, DMSO-d6): 1.91 (s, 3H), 2.35 (s, 4H); 3.17 (s, 2H), 3.57(t, J
= 4.4 Hz, 4H), 6.37 (s, 2H), 6.78 (d, J= 7.5 Hz, 1H), 7.13 (t, J= 7.8 Hz, 1H), 7.59 (s, 1H), 7.69 (s, 1H), 7.74 (d, J= 9.3 Hz, 1H), 8.68 (s, 1H).
EXAMPLE 137. N-tert-Buty1-3-15-methy1-243-morpho1in-4-ylmethy1-pheny1amino)-pyrimidin-4-ylaminol-benzenesulfonamide hydrochloride (Compound LVOCIX) HO
NH
6 N r0 N N
LVOCIX
[0288] A suspension of intermediate 50 (1.0 g, 3.42 minol), 3-bromo-N-tert-butyl-benzenesulfonamide (1.28 g, 4.28 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), Xantphos (40 mg, 0.07 mmol) and cesium carbonate (3.34 g, 10.24 mmol) in dioxane (50 mL) was degassed with argon for 2 min then refluxed for overnight. After cooling to room temperature, the solvent was removed by rotovap and the resulting mixture was purified by silica gel with 10% CH3OH/CHC13 as an eluent to afford the title compound as a white solid.
The white was dissolved in hot dioxane (150 mL) and titrated with 2 M HC1 in dioxane to pH
1. The solvent was removed by rotovap and the solid was recrystalized from methanol (0.15 g, 8%).
102891 1H NMR (500 MHz, DMSO-d6): 1.08 (s, 9H), 2.20 (s, 3H), 3.0-3.2 (in, 4H), 3.7-4.0 (m, 4H), 4.23 (s, 2H), 7.33 (t, J-= 7.9 Hz, 1H), 7.38 (d, J= 7.7 Hz, 1H), 7.48 (s, 1H), 7.55-7.65 (m, 3H), 7.71 (d, J= 7.9 Hz, 1H), 7.90 (d, J= 7.4 Hz, 1H), 8.01 (s, 1H), 9.96 (br s, 1H), 10.61 (br s, 1H), 11.31 (br s, 1H). MS (ES+): inlz 511 (M+H)+.
EXAMPLE 138. 2-Chloro-5-methyl-N-(3,5-dimethvlphenyl)pyrimidin-4-amine (Intermediate 51) NH
N
I
CI
[0290] A mixture of 1-bromo-3,5-dimethylbenzene (104 [IL, 0.77 mmol), 2-chloro-methyl-pyrimidin-4-ylamine (104 mg, 0.72 mmol), Pd(OAC)2 (15 mg, 0.07 mmol), Xantphos (83 mg, 0.14 mmol) and potassium tert-butoxide (159 mg, 1.42 mmol) in dioxane (8 mL) was microwaved at 160 C for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow oil (89 mg, 50%). MS (ES+): nez 248 (M+H)+.
EXAMPLE 139. 5-Methyl-/V4-(3.5-dimethylpheny1)-N2-(4-(piperidin-4-vloxy)phenyllpyrimidine-2,4-diamine (Compound XC1 N 0, NH
j.N)N
XC
[0291] A mixture of intermediate 51 (89 mg, 0.36 mmol), and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (139 mg, 0.47 mmol) in acetic acid was stirred at room temperature for 16h, then heated to 95 C for 2 h. The reaction mixture was concentrated in vacuo, and purified by preparative HPLC. The product was basified with NaHCO3 (aq)(10 mL) and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with brine (5 mL), dried (Na2SO4), and concentrated. The freebase was taken up in Me0H (5 mL) and conc HC1 (5 drops) and after 2 mm was concentrated in vacuo in the presence of DCM and hexanes to afford the HC1 salt of the title compound as an off-white solid (63 mg, 40%).
[0292] 111 NMR (500 MHz, DMSO-d6): 8 1.72-1.83.(m, 2H), 2.02-2.08 (m, 211), 2.14_(d, J
= 0.6 Hz, 311), 2.24 (s, 6H), 3.04-3.15 (m, 2H), 3.21-3.31 (m, 211), 4.57-4.60 (m, 1H), 6.85 (s, 111), 6.91 (d, J= 8.9 Hz, 211), 7.20 (s, 211), 7.37 (d, J= 8.9 Hz, 211), 7.85 (s, 1H), 8.50 (br s, 1H), 8.56 (br s, 1H), 9.36 (br s, 1H), 10.10 (br s, 1H). MS (ES+): ni/z 404 (M+H)+.
EXAMPLE 140. 2-Chloro-N-(3,5-dimethoxypheny1)-5-methylpyrimidin-4-amine (Intermediate 52) O NH
I
CI
[0293] A mixture of 1-bromo-3,5-dimethoxybenzene (436 mg, 2.01 mmol), 2-chloro-methyl-pyrimidin-4-ylamine (287 mg, 2.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), Xantphos (237 mg, 0.41 mmol) and potassium tert-butoxide (448 mg, 3.99 mmol) in dioxane (15 mL) and DMF (5 mL) was microwaved at 160 C for 20 mm. The reaction mixture was cooled to room temperature and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a yellow solid (182 mg, 33%).
[0294] NMR
(500 MHz, DMSO-d6): 6 2.17 (s, 3H), 3.74 (s, 6H), 6.27 (t, J= 2.2 Hz, 1H), 6.99 (d, i=2.2 Hz, 2H), 8.06 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 280 (M+H)+.
EXAMPLE 141. /V4-(3,5-Dimethoxypheny1)-5-methy1-N244-(piperidin-4-yloxy)phenybpyrimidine-2,4-diainine (Compound XCI) NH
N
I
N NH
XCI
[0295] A mixture of intermediate 52 (100 mg, 0.36 mmol), and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (106 mg, 0.36 mmol) in acetic acid was heated to 95 C for 2 h. The reaction mixture was concentrated in vacuo, and purified by preparative HPLC to afford the TFA salt of the title compound as a tan solid (75 mg, 39%).
[0296] NMR
(500 MHz, DMSO-d6): 5 1.74-1.83 (in, 2H), 2.03-2.11 (in, 2H), 2.15 (s, 3H), 3.06-3.15 (in, 2H), 3.21-3.30 (m, 2H), 3.69 (s, 6H), 4.57-4.60 (m, 1H), 6.39 (t, J- 2.2 Hz, 1H), 6.80 (d, J=2.2 Hz, 2H), 6.89 (d, J= 8.9 Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.86 (s, 1H), 8.53 (br s, 1H), 8.58 (br s, 1H), 9.49 (br s, 1H), 10.24 (br s, 1H). MS
(ES+): in/z 436 (M+H)+.
EXAMPLE 142. 5-Methyl-N2-(4-(4-methylpiperazin-1-yl)pheny1)-/V4-(3-(piperidin-yl)phenybpyrimidine-2,4-diamine (Compound XCII), N el NH
I
N
XCII
[0297] A mixture of 1-(3-bromophenyl)piperidine (91 mg, 0.38 mmol), intermediate 32 (99 mg, 0.33 mmol), Pd2(dba)3 (15 mg, 0.02 mmol), Xantphos (24 mg, 0.04 mmol) and cesium carbonate (219 mg, 0.67 mmol) in dioxane (4 mL) was microwaved at 160 C for 15 min. The reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in methanol, and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified by preparative HPLC to afford the TFA salt of the title compound as an off-white solid (14 mg, 8%).
[0298] 11-1NMR (500 MHz, DMSO-d6): 5 1.47-1.53 (m, 2H), 1.56-1.61 (m, 4H), 2.07 (s, 3H), 2.21 (s, 3H), 2.44 (t, J=4.9 Hz, 4H), 3.01 (t, J-4.9 Hz, 4H), 3.08 (t, J5.4 Hz, 4H), 6.63 (dd, J = 8.2, 2.3 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H), 7.12 (t, J= 8.3 Hz, 1H), 7.14 (s, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.81 (s, 1H), 8.00 (s, 1H), 8.67 (s, 1H). MS
(ES+): ni/z 458 (M+H)+.
EXAMPLE 143. N4-(341H-Pyrrol-1-y1)pheny1)-5-methyl-N2-(4-(4-methylpiperazin-1-ybphenyl)pyrimidine-2,4-diamine (Compound XCIII) el el NH N-- N N) N
[0299] A mixture of 1-(3-bromopheny1)-1H-pynole (86 mg, 0.39 mmol), intermediate 32 (99 mg, 0.33 mmol), Pd2(dba)3 (16 mg, 0.02 mmol), Xantphos (26 mg, 0.05 mmol) and cesium carbonate (215 mg, 0.66 nunol) in dioxane (4 mL) was microwaved at 160 C for 15 mm. The reaction mixture was cooled to room temperature, concentrated in vacuo, taken up in methanol, and filtered rinsing with DCM and methanol. The filtrate was concentrated and purified by preparative HPLC to afford the TFA salt of the title compound as an off-white solid (32 mg, 18%).
[0300] 1H NMR (500 MHz, DMSO-d6): 8 2.11 (s, 3H), 2.21 (s, 3H), 2.42 (t, J=4.9 Hz, 4H), 2.95 (t, J=4.9 Hz, 4H), 6.24 (t, J=2.2 Hz, 2H), 6.58 (d, J=8.9 Hz, 2H), 7.23 (dd, J-7 .8, 1.8 Hz, 1H), 7.31 (t, J= 2.2 Hz, 2H), 7.37 (t, J=8.1 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.86 (t, J=2.2 Hz, 1H), 7.87 (s, 1H), 8.30 (s, 1H), 8.74 (s, 1H). MS
(ES+): m/z 440 (M+H)+.
EXAMPLE 144. 5-1244-(1-tert-Butoxycarbonyl-piperidin-4-yloxy)-phenylaminol-5-methyl-pyrimidin-4-ylaminol-indole-1-carboxylic acid tert-butyl ester (Intermediate 53) NyO
N
NH
N
[0301] A mixture of tert-butyl 5-bromo-1H-indole-1-carboxylate (161 mg, 0.54 mmol), intermediate 42 (202 mg, 0.50 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), Xantphos (36 mg, 0.07 mmol) and cesium carbonate (321 mg, 0.98 mmol) in dioxane (5 mL) was microwaved at 160 C for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM. The filtrate was concentrated and purified by gradient flash chromatography (0-20% Me0H in DCM) to afford the title compound as a light-brown solid (290 mg, 94%).
MS (ES+): nilz 615 (M+H)+.
=
EXAMPLE 145. N4-(1H-Indol-5-y1)-5-methyl-N2-0-(Piperidin-4-vioxy)phenyi)pyrimidine-214-diamine (Compound XCI'V) NH
NN NH
40) XCIV
[03021 To a solution of acetyl chloride (670 pL, 9.42 mmol) in methanol (22 mL) was added intermediate 53 (290 mg, 0.47 mmol), and the reaction mixture was heated to 60 C for 4 h. The mixture was concentrated in vacuo and purified by preparative HPLC to afford the TFA salt of the title compound as a brown solid (6 mg, 2%).
[03031 1H NMR (500 MHz, DMSO-d6): 8 1.70-1.78 (m, 2H), 1.98-2.07 (m, 2H), 2.16 (s, 3H), 3.02-3.11 (m, 2H), 3.21-3.30 (m, 2H), 4.44-4.53 (m, 1H), 6.43 (s, 1H), 6.75 (d, J= 8.2 Hz, 2H), 7.16 (d, J= 8.4 Hz, 1H), 7.31 (d, J 8.7 Hz, 2H), 7.40-7.42 (m, 2H), 7.71 (s, 1H), 7.78 (s, 1H), 8.48 (br s, 1H), 8.54 (br s, 1H), 9.65 (br s, 1H), 9.99 (br s, 1H), 11.18 (s, 1H).
MS (ES+): nilz 415 (M+H)+.
EXAMPLE 146. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(6-piperazin-1-171-pyridin-3-14)-pyrimidine-2,4-diamine (Compound XCV) CI
N
NNN
XCV
[03041 A mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(5-amino-pyridin-2-y1)-piperazine-1-carboxylic acid tert-butyl ester (0.10 g, 0.36 mmol), Pd2(dba)3 (30 mg, 0.033 Xantphos (35 mg, 0.06 nunol) and cesium carbonate (0.23 g, 0.71 mmol) in dioxane/DMF (3/1, 4 triL) was sealed in a microwave reaction tube and irradiated with microwave at 170 C for 30 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to Et0Ac) to afford the Boc-protected precursor. To a solution of the precursor in DCM (5 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 30 min, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the resulting solid triturated in a mixture of hexanes/Et0Ac (10/1, 55 mL). After filtration, the title compound was obtained as a white solid (20 mg, 13%).
[0305] 1H NMR (500 MHz, DMSO-d6): 6 2.09 (s, 3H), 2.81 (t, J= 5.0 Hz, 4H), 3.29-3.31 (m, 4H), 3.73 (s, 3H), 6.70 (d, J= 9.1 Hz, 1H), 7.26 (d, J= 8.6 Hz, 1H), 7.42 (d, J= 9.1 Hz, 1H), 7.49 (d, J= 2.2 Hz, 1H), 7.76 (dd, .1= 9.1, 2.6 Hz, 1H), 7.86 (s, 1H), 8.29 (s, 1H), 8.31 (d, J¨ 2.6 Hz, 1H), 8.71 (s, 1H). MS (ES+): ni/z 426 (M+H)+.
EXAMPLE 147. 4-(4-Amino-2-methoxycarbonvi-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (Intermediate 54) NBoc [0306] To a solution of 4-(2-methoxycarbony1-4-nitro-pheny1)-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 2.7 mmol) in Me0H (30 mL) was added 10 wt% Pd/C
(0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 2 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo.
The crude amino-compound was used in the next step without purification. MS (ES+): tn/z (M+H)+, EXAMPLE 148. 544-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylamino1-2-piperazin4-yl-benzoie acid methyl ester (Compound XCVI1 CI
NH 0 r.NH
NN
I
XCVI
[0307] A mixture of intermediate 31 (0.10 g, 0.35 mmol), intermediate 54 (0.14 g, 0.42 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) was suspended in dioxane (15 mL) and heated at reflux under the argon atmosphere for 2.5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60% Et0Ac/hexanes) to afford the Boc-protected precursor. To a solution of the precursor in DCM (5 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and = filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 24%).
[0308] 1H NMR (500 MHz, DMSO-d6): 32.11 (s, 3H), 2.80-2.90 (m, 8H), 3.73 (s, 3H), 3.74 (s, 3H), 6.98 (d, J= 8.9 Hz, 1H), 7.25 (d, J= 8.5 Hz, 1H), 7.40-7.48 (in, 2H), 7.69 (dd, J
---- 8.9, 2.6 Hz, 1H), 7.90 (d, J= 2.6 Hz, 1H), 7.91 (s, 1H), 8.36 (s, 1H), 9.04 (s, 1H). MS
(ES+): m/z 483 (M+H)+.
EXAMPLE 149. 5-Amino-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (Intermediate 55) 0,,No =
[0309] A suspension of 5-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6.0 mmol), 1-(2-chloro-ethyl)-pynolidine hydrochloride (1.2 g, 7.1 mmol) and cesium carbonate (5.0 g, 15 mmol) in DMF (40 mL) was heated at 60 C for 17 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with Et0Ac (2 x 50 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue purified by flash chromatography on silica gel (DCM to 30% Me0H/DCM) to afford the title compound (0.2 g, 13%) as a light brown solid.
MS (ES+): m/z 265 (M+H)+.
EXAMPLE 150. 5-[4-(Benzo[(31dioxo1-4-ylamino)-5-methyl-pyrimidin-2-ylamino1-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid methyl ester (Compound XCVII) NH
\/L
N NO
-N N
XCVII
[0310] A mixture of intermediate 30 (0.15 g, 0.57 mmol), intermediate 55 (0.20 g, 0.75 mmol), Pd2(dba)3 (50 mg, 0.055 mmol), Xantphos (60 mg, 0.10 mmol) and cesium carbonate (0.30 g, 0.92 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (30 mg, 11%).
[0311] 1H NMR (500 MHz, DMSO-d6): 5 1.65-1.72 (m, 4H), 2.07 (s, 3H), 2.50-2.62 (m, 4H), 2.75-2.85 (m, 2H), 3.73 (s, 3H), 4.02 (t, J 5.8 Hz, 2H), 5.88 (s, 2H), 6.78-6.88 (m, 3H), 6.92 (dd, J= 8.0, 2.1 Hz, 1H), 7.75-7.80 (m, 2H), 7.83 (s, 1H), 8.22 (s, 1H), 8.89 (s, 1H). MS (ES+): in/z 492 (M+H)+.
EXAMPLE 151. N-tert-Buty1-3-{5-methy1-2-14-(piperidin-4-yloxy)-phenylaminol-pyrimidin-4-ylamino}-benzenesulfonamide (Compound XCVIII) A Si NH
=i \ =
NN NH
XCVIII
[0312] A mixture of intermediate 33 (0.15 g, 0.42 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.15 g, 0.51 rrunol) in acetic acid (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 150 C
for 20 min.
After cooling to room temperature, the cap was removed and the mixture concentrated. The residue was taken in water (20 mL) and the pH adjusted with 10% NaOH solution until solid precipitated. The solid was filtered and then purified by HPLC. The corrected fractions were combined, poured into saturated NaHCO3 solution (30 mL) and extracted with Et0Ac (2 x 30 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (20 mg, 9%).
[0313] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 1.65-1.73 (m, 2H), 1.95-2.05 (m, 2H), 2.12 (s, 3H), 2.89-2.95 (m, 2H), 3.10-3.20 (m, 2H), 4.40 /1.45 (m, 1H), 6.84 (d, .1= 9.1 Hz, 2H), 7.45-7.60 (m, 6H), 7.90 (s, 1H), 8.10-8.15 (m, 2H), 8.55 (s, 1H), 8.81 (s, 1H). MS
(ES+): m/z 511 (M+H) .
EXAMPLE 152. 2-(5-Amino-pyridin-2-yloxy)-ethanol (Intermediate 56) OH
[0314] To a solution of 2-(5-nitro-pyridin-2-yloxy)-ethanol (1.0 g, 5.4 mmol) in Me0H
(30 mL) was added 10 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 1 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS (ES+): in/z 155 (M+H)+.
EXAMPLE 153. 2-{5-[4-(Senzo[1,3]dioxol-4-ylarnino)-5-methyl-pyrimidin-2-ylamino]-pyridin-2-yloxyl-ethanol (Compound XCIX) NH
r()OH
NNN
XCIX
[0315] A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 56 (0.10 g, 0.65 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.26 g, 0.80 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (50 mg, 35%).
[0316] 1H NMR (500 MHz, DMSO-do): 5 2.06 (s, 3H), 3.66 (q, J= 5.4 Hz, 2H), 4.15 (t, J
= 5.2 Hz, 2H), 4.77 (t, J= 5.5 Hz, 2H), 5.91 (s, 2H), 6.52 (d, J = 9.0 Hz, 1H), 6.78-6.90 (m, 3H), 7.82 (s, 1H), 7.96 (dd, J= 8.9, 2.7 Hz, 1H), 8.22 (d, J= 2.6 Hz, 1H), 8.27 (s, 1H), 8.84 (s, 1H). MS (ES+): m/z 382 (M+H)+.
EXAMPLE 154. 142-(2-Methoxy-4-nitro-phenoxy)-ethyThpyrrolidine (Intermediate [0317] A suspension of potassium 2-methoxy-4-nitro-phenolate (2.0 g, 9.7 mmol), 142-chloro-ethyp-pyrrolidine hydrochloride (2.0 g, 12 mmol) and cesium carbonate (7.0, 22 mmol) in DMF (35 mL) was heated at 80 C for 16 h. The mixture was allowed to cool to room temperature, poured into water (60 mL) and extracted with Et0Ac (2 x 50 mL). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and used in the next step without purification.
MS (ES+): m/z 267 (M+H)+. =
EXAMPLE 155. 3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (Intermediate [03181 To a solution of intermediate 57 (1.7 g, 6.4 nunol) in Me0H (30 mL) was added 10 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated and then refilled with hydrogen (3 cycles) and stirred at room temperature for 1 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS
(ES+): m/z 237 (M+H)+.
EXAMPLE 156. N4-Benzo[1,31dioxo1-4-yl-N2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-pheny11-5-methyl-pyrimidine-2,4-diamine (Compound C) N
[03191 A mixture of intermediate 30 (0.10 g, 0.38 mmol), interniediate 58 (0.11 g, 0.46 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (50 mg, 28%).
[0320] 1H NMR (500 MHz, DMSO-d6): 5 1.65-1.72 (in, 4H), 2.06 (s, 3H), 2.50-2.62 (m, 4H), 2.75-2.85 (m, 2H), 3.50 (s, 3H), 3.94 (t, J= 6.1 Hz, 2H), 5.84 (s, 2H), 6.67 (d, J= 8.8 Hz, 1H), 6.78 (dd, J= 7.8, 1.1 Hz, 1H), 6.83 (t, J= 7.9 Hz, 1H), 6.92 (dd, J=
8.1, 1.1 Hz, 1H), 7.14 (dd, J= 8.7, 2.4 Hz, 1H), 7.23(d, I-- 2.4 Hz, 1H), 7.83 (s, 1H), 8.21 (s, 1H), 8.69 (s, 1H). MS (ES+): m/z 464 (M+H)+.
EXAMPLE 157. N-tert-Buty1-342-(4-imidazol-1-yl-phenylamino)-5-methyl-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CI) /S\ NH
0"0 N/>
t 40 N N
CI
[0321] A mixture of intermediate 33 (0.40 g, 1.1 mmol), 4-imidazol-1-yl-phenylamine (0.20 g, 1.3 mmol), Pd2(dba)3 (0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (0.80 g, 2.5 mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 30 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (40 mL). The combined aqueous layers were extracted with Et0Ac (2 x 40 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (0.15 g, 28%).
[0322] 1H NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.15 (s, 3H), 7.07 (s, 1H), 7.43 (d, J¨ 9.0 Hz, 2H), 7.50-7.60 (m, 3H), 7.61 (s, 1H), 7.79 (d, J = 9.0 Hz, 2H), 7.98 (s, 1H), 8.08-8.13 (m, 3H), 8.64 (s, 1H), 9.19 (s, 1H). MS (ES+): m/z 478 (M+H)+.
EXAMPLE 158. N-tert-Buty1-3-f2-(4-imidazo1-1-y1methyl-pheny1amino)-5-methy1-pyrimidin-4-ylamino]-benzenesulfonamide (Compound CII) NH
NH
0"0 NI
I
N
CII
[0323] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-imidazol-1-ylmethyl-phenylamine (60 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The -filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 29%).
[0324] NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.13 (s, 3H), 5.07 (s, 2H), 6.89 (s, 1H), 7.12 (d, J= 8.6 Hz, 2H), 7.15 (s, 1H), 7.46 (t, J= 7.9 Hz, 1H), 7.49-7.52 (m, 1H), 7.56 (s, 1H), 7.63 (d, J= 8.6 Hz, 2H), 7.72 (s, 1H), 7.94 (s, 1H), 8.09 (s, 1H), 8.14 (d, J= 8.1 Hz, 1H), 8.60 (s, 1H), 9.02 (s, 1H). MS (ES+): m/z 492 (M+H)+.
EXAMPLE 159. 2-(4-Amino-phenoxy)-ethanol (Intermediate 59) [0325] A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in Me0H
(30 mL) was flushed with argon and then charged with 10 wt% Pd/C (0.1 equiv by wt). The mixture was evacuated under house vacuum and then refilled with hydrogen from hydrogen balloon. The cycle was repeated again and the mixture stirred at room temperature for 2 h.
The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo to furnish the title compound (1.8 g, 99%) as a brown solid. MS
(ES+): in/z 154 (M+H)+.
EXAMPLE 160. N-tert-Buty1-3-{244-(2-hydroxy-ethoxy)-pheny1amino1-5-methy1-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CIII) NH
O"O
OH
N N
CIII
[0326] A mixture of intermediate 33 (0.10 g, 0.28 nu-nol), intermediate 59 (55 mg, 0.36 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).
[0327] 1HNMR (500 MHz, DMSO-d6): 5 1.12 (s, 9H), 2.12 (s, 3H), 3.69 (q, J =
5.2 Hz, 2H), 3.91 (t, J = 5.1 Hz, 2H), 4.82 (t, J= 5.5 Hz, 2H), 6.80 (d, J= 9.1 Hz, 2H), 7.45-7.50 (m, 2H), 7.52 (d, J=-= 9.0 Hz, 2H), 7.55 (s, 1H), 7.90 (s, IH), 8.08-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): Tn/z 472 (M+H)+.
EXAMPLE 161. N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N244-piperazin-1-ylmethyl-pheny1)-pyrimidine-2,4-diarnine (Compound CIV), CI
NH
N4 Nr.'" 10 NN (=õ,õNH
CIV
[0328] A
mixture of intermediate 31 (0.10 g, 0.35 mmol), 4-(4-amino-benzy1)-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in dioxane/DMF
(3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C
for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM and the filtrate concentrated. The residue was purified by flash chromatography on silica gel (hexanes to 60%
Et0Ac/hexanes) to afford the Boc-protected precursor. To a solution of the precursor in DCM
(5 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 1 h, concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (13 mg, 9%).
[0329] NMR
(500 MHz, DMSO-d6): 8 2.11 (s, 3H), 2.30-2.40 (m, 4H), 2.83 (t, J= 4.8 Hz, 4H), 3.37 (s, 2H), 3.75 (s, 3H), 7.08 (d, J= 8.6 Hz, 2H), 7.29 (d, J= 8.6 Hz, 1H), 7.43 (dd, J= 8.6, 2.2 Hz, 1H), 7.47 (d, J= 2.2 Hz, 1H), 7.59 (d, J= 8.6 Hz, 2H), 7.91 (s, 1H), 8.37 (s, 1H), 8.99 (s, 1H). MS (ES+): nilz 439 (M+H)+.
EXAMPLE 162. N-tert-Buty1-3-{5-methyl-2-1.4(2-methy1-imidazo1-1-y1)-pheny1amino1-pyrimidin-4-y1aminol-benzenesu1fonamide (Compound CV).
H
>,N,/s\
NH
µ0 N
CV
[03301 A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(2-methyl-imidazol-1-y1)-phenylamine (60 mg, 0.35 nunol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (30 mg, 22%).
[03311 1H NMR (500 MHz, DMSO-d6): 8 1.11 (s, 9H), 2.15 (s, 3H), 2.24 (s, 3H), 6.87 (d, J= 1.2 Hz, 1H), 7.18 (d, J= 1.3 Hz, 1H), 7.22 (d, 8.9 Hz, 2H), 7.50-7.55 (m, 2H), 7.56 (s, 1H), 7.79 (d, 8.9 Hz, 2H), 7.98 (s, 1H), 8.07-8.10 (m, 2H), 8.65 (s, 1H), 9.26 (s, 1H).
MS (ES-0: m/z 492 (M+H)+.
EXAMPLE 163. N-tert-Buty1-3-{5-methy1-2-[442-methyl-imidazol-1-ylmethyl)-phenv1amino]-pyrimidin-4-y1aminol-benzenesu1fonamide (Compound CVI) H
NH
Ngki CVI
[0332] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(2-methyl-imidazol-1-ylmethyl)-phenylamine (65 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (30 mg, 21%).
[0333] 1H NMR (500 MHz, DMSO-d6): 1.12 (s, 9H), 2.13 (s, 3H),2.24 (s, 3H), 5.01 (s, 2H), 6.73 (d, J= 1.2 Hz, 1H), 7.01 (d, J= 8.6 Hz, 2H), 7.07 (d, J= 1.1 Hz, 1H), 7.44 (t, J=
7.9 Hz, 1H), 7.48-7.51 (m, 1H), 7.56 (s, 1H), 7.62 (d, J= 8.6 Hz, 2H), 7.94 (s, 1H), 8.08 (s, 1H), 8.12 (d, J= 8.1 Hz, 1H), 8.60 (s, 1H), 9.02 (s, 1H). MS (ES+): m/z 506 (M+H)4r.
EXAMPLE 164. N-tert-Buty1-3-1-5-methy1-244-pyridin-4-ylmethyl-phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CVII) /Sµ\ NH
t I N
N N
CVII
[0334] A mixture of inteunediate 33 (0.10 g, 0.28 mmol), 4-Pyridin-4-ylmethyl-phenylamine (65 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (45 mg, 32%).
[0335] 11-1NMR (500 MHz, DMSO-d6): 8 1.11 (s, 9H), 2.13 (s, 3H), 3.87 (s, 2H), 7.07 (d, J= 8.6 Hz, 2H), 7.22 (d, J= 6.0 Hz, 2H), 7.43 (t, J= 7.9 Hz, 1H), 7.47-7.50 (m, 1H), 7.56 (d, J= 6.3 Hz, 2H), 7.58 (s, 1H), 7.93 (s, 1H), 8.09 (s, 1H), 8.13 (d, J= 8.0 Hz, 1H), 8.44 (d, J= 5.8 Hz, 2H), 8.58 (s, 1H), 8.94 (s, 1H). MS (ES+): ni/z 503 (M+H)+.
EXAMPLE 165. N-tert-Buty1-345-methyl-244-morpholin-4-yl-phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CVIII) >N1-1,./s\
NH ro 0-0 ),õ
=
CVIII
[0336] A mixture of intetinediate 33 (0.10 g, 0.28 mmol), 4-morpholin-4-yl-phenylamine (60 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a grey solid (45 mg, 32%).
[0337] 1H NMR (500 MHz, DMSO-d6): 8 1.12 (s, 9H), 2.12 (s, 3H), 3.00 (t, J=
4.8 Hz, 4H), 3.73 (t, J= 4.8 Hz, 4H), 6.82 (d, Jr 9.1 Hz, 2H), 7.45-7.52 (m, 4H), 7.56 (s, 1H), 7.89 (s, 1H), 8.10-8.17 (m, 2H), 8.52 (s, 1H), 8.73 (s, 1H). MS (ES+): nilz 497 (M+H) .
EXAMPLE 166. N-tert-Buty1-3-[5-methy1-2-(441,2,41triazol-1-ylmethyl-phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CIX) H
>,N NH
,./" s\
N N-N N
CIX
=
[0338] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-[1,2,4]triazo1-1-y1methyl-phenylamine (60 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 rnmol), Xantphos (30 mg, 0.052 mm.ol) and cesium carbonate (0.20 g, 0.61 rnmol)in dioxane (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (37 mg, 27%).
[0339] 11-1 NMR (500 MHz, DMSO-d6): 8 1.17 (s, 9H), 2.13 (s, 3H), 5.29 (s, 2H), 7.14 (d, J= 8.6 Hz, 2H), 7.46 (t, J 7.8 Hz, 1H), 7.48-7.51 (m, 1H), 7.56 (s, 1H), 7.63 (d, 8.6 Hz, 2H), 7.94 (s, 1H), 7.95 (s, 1H), 8.08 (s, 1H), 8.13 (d, J= 8.0 Hz, 1H), 8.59 (s, 1H), 8.60 (s, 1H), 9.04 (s, 1H). MS (ES+): nilz 493 (M+H)+.
EXAMPLE 167. N-tert-Buty1-3-{5-methyl-2-[4-(4-methyl-imidazol-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CX) H
NH ,-N
\O NN
CX
[0340] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(4-methy1-imidazol-1-y1)-phenylamine (60 mg, 0.35 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac'(2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (20 mg, 15%).
[03411 1H NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.15 (s, 3H), 2.16 (s, 3H), 7.30 (s, 1H), 7.38 (d, J= 9.0 Hz, 2H), 7.50-7.56 (m, 2H), 7.57 (s, 1H), 7.76 (d, J¨ 9.0 Hz, 2H), 7.96 (s, 1H), 7.97 (s, 1H), 8.09-8.13 (m, 2H), 8.63 (s, 1H), 9.16 (s, 1H). MS
(ES+): in/z 492 (M+H)4- .
EXAMPLE 168. N-tert-Butyl-3-[5-methyl-2-(4-[1,2,4]triazol-1-yl-phenvlamino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXI) H
NH N=--\
0/ 0N,N
N
CXI
[0342] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 441,2,4]triazol-1-yl-phenylamine (55 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 ni.M.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na?Sat and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 29%).
[0343] 1H NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.15 (s, 3H), 7.50-7.58 (m, 3H), 7.63 (d, J= 9.1 Hz, 2H), 7.83 (d, J= 9.0 Hz, 2H), 7.99 (s, 1H), 8.09 (s, 1H), 8.10-8.15 (m, 1H), 8.17 (s, 1H), 8.66 (s, 1H), 9.12 (s, 1H), 9.27 (s, 1H). MS (ES+): m/z 479 (M+H)+.
EXAMPLE 169. N-tert-Butv1-3-{5-methyl-2-[341H-tetrazol-5-y1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXII) N,F1 NH
HN-N
CXII
[0344] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 3-(1H-tetrazol-5-y1)-phenylamine (55 mg, 0.34 mmol), Pd2(dba)3 (25 mg, 0.027 nunol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 nit) was sealed in a microwave reaction tube and irradiated with microwave at 160 C. for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with EtOAc (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).
[0345] 1H NMR (500 MHz, DMSO-d6): 61.13 (s, 9H), 2.15 (s, 3H), 7.26 (t, J=
7.9 Hz, 1H), 7.38 (t, J= 8.0 Hz, 1H), 7.44 (dd, J= 7.9, 1.1 Hz, 1H), 7.50 (d, J= 7.6 Hz, 1H), 7.58 (s, 1H), 7.79 (dd, J= 8.1, 1.4 Hz, 1H), 7.98 (s, 1H), 8.16 (s, 1H), 8.22 (s, 1H), 8.27 (d, J= 7.8 Hz, 1H), 8.57 (s, 1H), 9.08 (s, 1H). MS (ES+): m/z 480 (M+H)+
EXAMPLE 170. 4(1H-Tetrazol-5-y1)-phenylamine (Intermediate 60) HN
[0346] To a solution of 5-(4-nitro-phenyl)-1H-tetrazole (1.0 g, 5.2 mmol) in Me0H (30 mL) was added 10 wt% Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated, refilled with hydrogen (3 cycles) and stirred at room temperature for 1.5 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with Me0H and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS (ES+): nilz 162 (M+H)+.
EXAMPLE 171. N-tert-Buty1-3-{5-methyl-2-14-(1H-tetrazol-5-y1)-phenylarninol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXIII) H
NH HN-1\,1, \O ,N
N 401 .1\1 CXIII
[0347] A mixture-of intennediate 33 (0.10 g, 0.28 mmol), intermediate 60 (60 mg, 0.37 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1; 4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 min. After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (15 mg, 11%).
[0348] 1H NMR (500 MHz, DMSO-d6): 5 1.13 (s, 9H), 2.16 (s, 3H), 7.52-7.56 (rn, 2H), 7.57 (s, 1H), 7.83 (s, 4H), 8.01 (s, 1H), 8.08 (s, 1H), 8.13-8.19 (m, 1H), 8.69 (s, 1H), 9.34 (s, 1H). MS (ES+): nz/z 480 (M+H)+ .
EXAMPLE 172. 3-1244-(4-Acetyl-piperazin-1-y1)-phenylaminol-5-methyl-pyrimidin-ylaminol-N-tert-butyl-benzenesulfonamide (Compound CXIV) // 1S\
N H N
\O
N
I
N
CXIV
[0349] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 144-(4-amino-phenyl)-piperazin-1-yll-ethanone (80 mg, 0.36 mmol), Pd2(dba)3 (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 C for 20 mm.
After cooling to room temperature, the cap was removed and the resulting mixture filtered. The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC. The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL). The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and then taken up in minimum amount of Et0Ac.
Hexanes were added until solid precipitated. After filtration, the title compound was obtained as an off white solid (55 mg, 37%).
[0350] 1H NMR (500 MHz, DMSO-d6): 6 1.12 (s, 9H), 2.04 (s, 3H), 2.12 (s, 3H), 2.97 (t, 5.2 Hz, 2H), 3.03 (t, J= 5.1 Hz, 2H), 3.57 (q, J---= 5.4 Hz, 4H), 6.85 (d, J=
9.0 Hz, 2H), 7.46-7.52 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H), 8.10-8.17 (m, 2H), 8.52 (s, 1H), 8.75 (s, 1H).
MS (ES+): m/z 538 (M+H)+.
EXAMPLE 173. N-tert-Butyl-3-{5-methyl-2-14-(1-morpholin-4-yl-ethyl)-phenylaminol-. Pvrimidin-4-ylamino}-benzenesulfonamide (Compound CXV) H
NH
C:L L
N N c) CXV
[0351] A mixture of intermediate 33 (0.10 g, 0.28 mmol), 4-(1-morpholin-4-yl-ethyl)-phenylamine (80 mg, 0.39 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (35 mg, 0.061 mmol) and cesium carbonate (0.26 g, 0.80 mmol) in dioxane (4 mL) was sealed in a microwave reaction tube and irradiated with microwave at 160 *C for 20 min.
After cooling to room temperature, the cap was removed and the resulting mixture filtered.
The filtered solid was washed with DCM, the filtrate concentrated and the residue purified by HPLC.
The corrected fractions were combined and poured into saturated NaHCO3 solution (30 mL).
The combined aqueous layers were extracted with Et0Ac (2 x 30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered.
The filtrate was concentrated and then taken up in minimum amount of Et0Ac. Hexanes were added until solid precipitated. After filtration, the title compound was obtained as a white solid (40 mg, 27%).
[0352] 1H NMR (500 MHz, DMSO-d6): 5 1.12 (s, 9H), 1.25 (d, J= 6.6 Hz, 3H), 2.13 (s, 3H), 2.20-2.30 (m, 2H), 2.30-2.40 (m, 2H), 3.24 (q, J= 6.6 Hz, 111), 3.54 (t, J= 4.4 Hz, 4H), 7.10 (d, J= 8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.55 (s, 1H), 7.57 (d, J= 8.5 Hz, 2H), 7.93 (s, 1H), 8.09 (s, 1H), 8.15 (d, J= 7.7 Hz, 1H), 8.57 (s, 1H), 8.92 (s, 1H). MS
(ES+): nilz 525 (M+H)+.
EXAMPLE 174. N441H-Indo1-4-y1)-5-methyl-N2-(4-(4-methylpiperazin-1-y1)phenyl)pyrirnidine-2,4-diamine (Compound CXVI) HN
IP NH
NN
CXVI
[0353] A mixture of intermediate 32 (270 mg, 0.9 mmol), 4-bromo-1H-indole (196 mg, 0.9 mmol), Pd2(dba)3 (91 mg, 0.09 mmol), Xantphos (157 mg, 0.27 mmol) and cesium carbonate (1.2 g, 3.6 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacua The residue was purified by HPLC to afford the title compound (55 mg of HCI salt, 14%) as a white solid.
[0354] IHNMR (500 MHz, DMSO-d6): 5 2.22 (s, 3H), 2.79 (d, J= 4.3 Hz, 3H), 2.98-3.03 (m, 2H), 3.08-3.14 (in, 2H), 3.46-3.48 (m, 2H), 3.64-3.66 (m, 2H), 6.35-6.36 (in, 1H), 6.63 (br d, J= 8.0 Hz, 1H), 6.98 (d, J¨ 9.1 Hz, 2H), 7.05 (d, J= 7.4 Hz, 1H), 7.16 (t, J= 7.6 Hz, 1H), 7.36 (t, J= 2.8 Hz, 2H), 7.43 (d, J= 8.0 Hz, 1H), 7.86 (s, 1H), 10.07 (s, 1H), 10.27 (s, 1H), 11.00 (br s, 1H), 11.38 (s, 1H), 12.16 (br s, H). MS (ES+): m/z 414 (M+H)+.
EXAMPLE 175. 2-Chloro-5-methyl-N-(2,3-dimethylphenyl)pyrimidin-4-amine (Intermediate 61) lel NH
N
CI
[0355] A mixture of 2-chloro-5-methylpyrimidin-4-amine (143.6 mg, 1 mmol), 1-bromo-2,3-dimethylbenzene (222 mg, 1.2 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (174 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (150 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in Et0Ac (10 mL) and added hexanes (100 mL). The solid was collected by filtration and washed with hexanes to afford the crude title compound as a yellow solid.
EXAMPLE 176. 5-Methyl-N4-(2,3-dimethylphenyI)-N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine (Compound CXVII), N (3' I NH
N
CXVII
[0356] A mixture of intermediate 61 (1.0 mmol) and tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (292.4 mg, 1.0 mmol) were suspended in acetic acid (10 mL) and heated at 100 C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (105 mg of HC1 salt, 24%) as a yellow solid.
[0357] 1H NMR (500 MHz, DMSO-do): 8 1.76-1.83 (m, 2H), 2.03 (s, 3H), 2.05-2.09 (m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 3.02-3.05 (m, 2H), 3.18 (br s, 2H), 4.53-4.56 (m, 1H), 6.72 (d, J= 8.5 Hz, 2H), 7.11-7.14 (m, 3H), 7.19-7.24 (m, 2H), 7.87 (s, 1E), 9.06 (br s, 1H), 9.13 (br s, 1H), 9.92 (s, 1H), 10.43 (s, 1H). MS (ES+): in/z 404 (M+H)+.
EXAMPLE 177. /V144-Chloro-3,5-dimethylpheny1)-5-methyl-N2-(4-(4-methylpiperazin-1-yl)phenybpyrimidine-2,4-diamine (Compound CXVIII) CI is N
NH
N N
N
CX VIII
[0358] A mixture of intelinediate 32 (240 mg, 0.8 mmol), 5-bromo-2-thloro-1,3-dimethylbenzene (212 mg, 0.96 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (170 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (63 mg of HC1 salt, 17%) as a white solid.
[0359] IHNMR (500 MHz, DMSO-d6): 5 2.15 (s, 3H), 2.17 (s, 3H), 2.80 (d, J=
4.5 Hz, 3H), 3.06-3.14 (m, 4H), 3.48-3.52 (m, 2H), 3.75-3.77 (m, 2H), 6.93 (d, J= 8.9 Hz, 2H), 7.29 (d, J= 8.9 Hz, 2H), 7.46 (s, 2H), 7.90 (s, 1H), 9.65 (s, 1H), 10.49 (s, 1H), 11.13 (br s, 2H).
MS (ES+): inlz 437 (M+H)+.
EXAMPLE 178. N2-(4-(2-(Pyrrolidin-1-vbethoxy)phenv1)-10-(3-tert-butylpheny1)-5-methyl-pyrimidine-2,4-diamine (Compound CXIX) N
I
N
CXIX
[0360] A mixture of intermediate 41 (365 mg, 1.32 mmol) and 4-(2-(pyrro1idin-1-yl)ethoxy)benzenamine (410 mg, 1.98 mmol) were suspended in acetic acid (20 mL) and heated at 100 C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (127 mg of HC1 salt, 20%) as a white solid.
[0361] 1HNMR (500 MHz, DMSO-d6): 6 1.89-1.91 (m, 2H), 1.98-2.02 (m, 2H), 2.17 (s, 3H), 3.07-3.12 (m, 2H), 3.52-3.57 (m, 4H), 4.32 (t, J 4.8 Hz, 2H), 6.90 (d, J=
8.9 Hz, 2H), 7.29-7.38 (in, 4H), 7.43-7.44 (m, 1H), 7.48 (d, 7.9 Hz, 1H), 7.89 (s, 1H), 9.75 (s, 1H), 10.51 (s, 1H), 11.07 (br, 1H). MS (ESI+): in/z 446 (M+H)+.
EXAMPLE 179. N2-(4-(2-(Pyrrolidin-l-yl)ethoxy)pheny1)44-(4-(3-tert-butylphenyinmino)-5-methylpyrimidin-2-y1)-5-methylpyrimidine-2,4-diamine (Compound CXX1 qiir NH
"N
I
CXX
[0362] A mixture of intermediate 41 (210 mg, 0.67 mmol), intermediate 38 (185 mg, 0.67 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 g, 2.4 mmol) were suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (94 mg of HC1 salt, 24%) as a yellow solid.
[0363] 1H NMR (500 MHz, DMSO-d6): 6 1.29 (s, 9H), 1.84-1.88 (m, 2H), 1.94-2.01 (m, 2H), 2.14 (s, 3H), 2.27 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.56 (m, 4H), 4.29 (t, J-- 4.9 Hz, 2H), 6.97 (d, J= 9.1 Hz, 2H), 7.27 (d, J= 8.6 Hz, 2H), 7.34 (t, J¨ 7.9 Hz, 2H), 7.57 (t, J-1.9 Hz, 2H), 7.65 (d, J= 9.1 Hz, 1H), 7.72 (d, J¨ 8.6 Hz, 2H), 8.15 (s, 1H), 8.39 (s, 1H), 9.82 (s, 1H), 10.21 (br s, 1H), 10.68 (hr s, 1H), 10.93 (hr s, 1H). MS (ES+):
tn/z 553 (M+H)+.
EXAMPLE 180. 5-Methyl-N244-(4-methyl-piperazin-1-y1)-phenyll-N4-[3-(piperidine-sulfony)-phenyll-pyrimidine-2,4-diamine (Compound cxxi) o,s/Pd r la NH
N N'') CXXI
[0364] A mixture of intermediate 32 (150 mg, 0.5 mmol), 1-(3-bromo-benzenesulfony1)-piperidine (152 mg, 0.5 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and cesium carbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (84 rng of HC1 salt, 37%) as a white solid.
[0365] 1H NMR (500 MHz, DMSO-d6): 8 1.30-1.34 (m, 2H), 1.50-1.55 (in, 4H), 2.17 (s, 3H), 2.81 (d, J= 4.5 Hz, 311), 2.88 (t, J= 5.3 Hz, 4H), 3.04-3.16 (m, 4H), 3.47-3.51 (m, 2H), 3.75-3.77 (m, 211), 6.33-6.34 (m, 1H), 6.95 (d, J= 9.0 Hz, 2H), 7.25 (d, J=
9.0 Hz, 2H), 7.56-7.63 (m, 2H), 7.83 (t, J= 1.7 Hz, 111), 7.92 (s, 1H), 8.05 (d, J= 9.3 Hz, 1H), 9.94 (s, 1H), 10.38 (s, 1H), 10.88 (br s, 1H). MS (ES+): rez 522 (M+H)+.
EXAMPLE 181. 5-Methyl-N2-14-(4-methyl-piperazin-1-y1)-phenyll-/V4-[3-(2-metlwl-piperidine-1-sulfony)-phenyll-pyrimidine-2,4-diamine (Compound CXXII) NH
---ACN N') CXXII
[0366] A mixture of intermediate 32 (161 mg, 0.54 mmol), 1-(3-bromo-benzenesulfony1)-2-methyl-piperidine (172 mg, 0.54 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and cesium carbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (10 mg of HC1 salt, 3%) as a white solid.
[0367] 1H NMR (500 MHz, DMSO-d6): 6 0.98 (d, J= 6.9 Hz, 311), 1.15-1.21 (m, 111), 1.36-1.40 (m, 311), 1.47-1.53 (m, 211), 2.18 (s, 3H), 2.80 (d, J= 4.5 Hz, 3H), 2.94-2.99 (m, 1H), 3.05-3.16 (m, 411), 3.47-3.49 (m, 211), 3.59-3.61 (m, 211), 3.73-3.76 (m, 2H), 4.08-4.10 (m, 1H), 6.93 (d, J= 8.9 Hz, 2H), 7.25 (d, J 8.9 Hz, 211), 7.58 (t, J= 8.0 Hz, 111), 7.65 (d, J
= 8.0 Hz, 1H), 7.92 (d, J = 7.1 Hz, 211), 7.96 (br, 111), 9.95 (s, 111), 10.45 (s, 111), 11.00 (br s, 111). MS (ES+): in/z 536 (M+H)+.
EXAMPLE 182. N-Cyclopenty1-3-{5-methy1-2-[4-(4-methyl-piperazin-1-y1)-phenylamino]-pyrimidine-4-ylaminol-benzenesulfonamide (Compound CXXIII) NH N-N') I
N
CXXIII
[0368] A mixture of intermediate 32 (229 mg, 0.78 mmol), 3-bromo-N-cyclopentyl-benzenesulfonamide (280 mg, 0.92 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (130 mg of HC1 salt, 25%) as a white solid.
[0369] 1HNMR (500 MHz, DMSO-d6): 6 1.27-1.36 (m, 4H), 1.36-1.58 (m, 4H), 2.18 (s, 3H), 2.80 (d, J= 4.6 Hz, 3H), 3.05-3.15 (m, 4H), 3.36-3.42 (m, 1H), 3.47-3.49 (m, 2H), 3.74-3.76 (m, 2H), 6.94 (d, J= 8.7 Hz, 2H), 7.26 (d, J= 8.9 Hz, 2H), 7.59 (t, J=
8.0 Hz, 1H), 7.68 (d, J= 8.0 Hz, 1H), 7.75(d, J= 7.1 Hz, 2H), 7.92 (br, 2H), 7.93 (br, 1H), 9.96 (s, 1H), 10.45 (s, 1H), 11.98 (br s, 1H). MS (ES+): m/z 522 (M+H)+.
EXAMPLE 183. 5-Methyl-N2-14-(4-methyl-piperazin-1-y1)-pheny11-1V4-13-(pyrrolidine-1-sulfony) phenyll-pyrimidine-2,4-diamine (Compound CXXIV) 0---zsLN
NH
N N') N
CXXIV
[0370] A mixture of inten-nediate 32 (298 mg, 1.0 mmol), 1-(3-bromo-benzenesulfony1)-pyrrolidine (360 mg, 1.24 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue Was purified by HPLC to afford the title compound (200 mg of HC1 salt, 37%) as a white solid.
[0371] 1H NMR (500 MHz, DMSO-d6): 8 1.61-1.65 (in, 4H), 2.19 (s, 3H), 2.80 (br, 3H), 3.06-3.16 (in, 10H), 3.74-3.77 (br, 2H), 6.94 (d, J= 9.0 Hz, 2H), 7.26 (d, J=
9.0 Hz, 2H), 7.60 (t, J= 8.0 Hz, 1H), 7.65 (d, J= 8.0 Hz, 1H), 7.91 (t, J= 1.7 Hz, 1H), 7.93 (s, 1H), 8.05 (d, J= 7.5 Hz, 1H), 9.95 (s, 1H), 10.43 (s, 1H), 11.07 (br s, 1H). MS (ES+):
nilz 508 (M+H)t EXAMPLE 184. /V4-[3-(2õ5-Dimethyl-pyrrolidine-1-sulfony1)-phenylf-5-methyl-N2-(4-methyl-piperazin-l-y1)-phenyll-pyrimidine-2,4-diamine (Compound CXXV) N
I
N
CXXV=
[0372] A mixture of intermediate 32 (298 mg, 1.0 mmol), 1-(3-bromo-benzenesulfony1)-- 2,5-dimethyl-pyrrolidine (318 mg, 1.0 mmol), Pd2(dba)3 (92 mg, 0.1 I-rump, Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (100 mg of HC1 salt, 17%) as a white solid.
[0373] 11-1 NMR (500 MHz, DMSO-d6): 8 1.26 (s, 3H), 1.27 (s, 3H), 1.45-1.48 (m, 4H), 2.19 (s, 3H), 2.80 (d, J= 4.6 Hz, 3H), 3.06-3.15 (m, 4H), 3.47-3.50 (m, 2H), 3.60-3.64 (m, 2H), 3.74-3.76 (in, 2H), 6.94 (d, J= 9.0 Hz, 2H), 7.25 (d, J= 9.0 Hz, 2H), 7.59 (t, J¨ 8.0 Hz, 1H), 7.68 (d, J= 7.6 Hz, 1H), 7.93 (br, 2H), 8.02 (br, 1H), 9.97 (s, 1H), 10.47 (s, 1H), 11.07 (br s, 1H). MS (ES+): m/z 536 (M+H)4-.
EXAMPLE 185. N-tert-Buty1-3-1-5-methy1-2-(4-piperazin-1-y1-pheny1amino)-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXVI1 r, /0 Liz7S-/-NH
NH
lei NH
N
CXXVI
[0374] A mixture of intermediate 33 (355 mg, 1.0 mmol), tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate (278 mg, 1.0 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in CH202 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH was added. The organic layer was separated and aqueous was extracted with CH2C12 (10 mL x 2). The combined organic layers were dried (Na2SO4).
The solvent was removed in vacuo. The residue was purified by HPLC to afford the title compound (62 mg, 12%) as a white solid.
[0375] 1H NMR (500 MHz, DMSO-d6): 5 1.10 (s, 9H), 2.18 (s, 3H), 3.20 (br, 4H), 3.33 (br, 4H), 6.94 (d, J= 9.0 Hz, 2H), 7.25 (d, J= 9.0 Hz, 2H), 7.57 (t, J= 8.0 Hz, 1H), 7.63 (s, 1H), 7.71 (d, J= 8.1 Hz, 1H), 7.87 (br, 1H), 7.92 (br, 1H), 7.96 (br, 1H), 9.30 (br, 1H), 9.96 (s, 1H), 10.46 (s, 1H). MS (ES+): m/z 496 (M+H)+.
EXAMPLE 186. N-tert-Buty1-3-(2-14-1-4-(2-hydroxy-ethyl)-piperazin-1-y11-phenylaminol-f5-methyl-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXVII) * NH NOH
N N
NN
CXXVII
[0376] The above-described compound CXXVI (31mg, 0.06 mmol) was dissolved in DMF (10 mL) followed by adding 2-bromoethanol (16 mg, 0.13 mmol) and diisopropylethylamine (33 mg, 0.25 mmol). The mixture was stirred for 48 h at room temperature. Solvent was removed in vacuo and residue was dissolved in Et0Ac (20 mL).
The solution was washed with saturated NaHCO3 and brine. The combined organic layers were dried and concentrated until 2 mL solution followed by adding Et20 (20 mL). The solid was collected by centrifugation and transferred to its HC1 salt (10.7 mg, 30%).
[0377] 1H NMR (500 MHz, DMSO-d6): 8 1.09 (s, 9H), 2.17 (s, 3H), 3.12-3.23 (in, 4H), 3.56-3.60 (m, 2H), 3.69-3.74 (m, 2H), 3.83 (br, 2H), 4.13 (br, 2H), 6.94 (d, J= 9.0 Hz, 2H), 7.25 (d, J= 9.0 Hz, 2H), 7.57 (t, J= 8.0 Hz, 1H), 7.63 (s, 1H), 7.71 (d, J=
8.1 Hz, 1H), 7.87 (br, 1H), 7.93 (br, 1H), 7.95 (br, 1H), 9.98 (s, 1H), 10.53 (s, 1H), 10.75 (br, 1H). MS (ES+):
m/z 540 (M+H)+.
EXAMPLE 187. N-tert-Butv1-345-methvi-2-(3-piperazin-1-0-phenylamino)-pyrimidin-4-vlaminol-benzenesulfonamide (Compound CXXVIIII
\<"
NH
õL
N
H NH
CXXVIII
[0378] A mixture of intermediate 33 (240 mg, 0.67 mmol), tert-butyl 4-(3-aminophenyl)piperazine-1-carboxylate (166 mg, 0.6 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in CH2C12 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH was added. The organic layer was separated and aqueous was extracted with CH2C12 (10 mL x 2). The combined organic layers were dried (Na2SO4).
The solvent was removed in vacuo. The residue was purified by HPLC to afford the title compound (18 mg, 6%) as a white solid.
[0379] 11-1NMR (500 MHz, DMSO-d6): 5 1.10 (s, 9H), 2.19 (s, 3H), 3.17 (br, 4H), 3.27-3.29 (m, 4H), 6.80 (d, J= 8.1 Hz, 1H), 6.87 (br, 1H), 6.96 (d, J= 8.1 Hz, 1H), 7.16(t, J= 8.1 Hz, 1H), 7.53 (t, J= 8.3 Hz, 1H), 7.61 (s, 1H), 7.70 (d, J= 7.8 Hz, 1H), 7.94 (br, 3H), 9.19 (br, 2H), 9.93 (s, 1H), 10.48 (s, 1H). MS (ES+): m/z 496 (M+H)+.
EXAMPLE 188. N-tert-Butv1-342-{3-[4-(2-hydroxy-ethyl)-piperazin-1-y1]-phenylaminol-[5-methyl-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXIX) n /0 H
NH
N
N OH
CXXLX
[0380] The above-describeed compound CXXVI (12mg, 0.024 mmol) was dissolved in DMF (10 mL) followed by adding 2-bromoethanol (6.1 mg, 0.048 mmol) and diisopropylethylamine (12 mg, 0.092 mmol). The mixture was stirred for 48 h at room temperature. Solvent was removed in vacuo and residue was dissolved in Et0Ac (20 mL).
The solution was washed with saturated NaHCO3 and brine. The combined organic layers were dried and concentrated until 2 mL solution followed by adding Et20 (20 mL). The solid was collected by centrifugation and transferred to its HC1 salt (7 mg, 51%).
[0381] 1H NMR (500 MHz, DMSO-d6): 5 1.09 (s, 9H), 2.19 (s, 3H), 3.12-3.22 (m, 4H), 3.56-3.60 (m, 2H), 3.69-3.74 (m, 2H), 3.81 (br, 2H), 4.12 (br, 2H), 6.80 (br, 1H), 6.88 (br, 1H), 6.96 (br, 1H), 7.16 (br, 1H), 7.57 (br, 1H), 7.60 (s, 1H), 7.69 (d, J=
7.8 Hz, 1H), 7.94 (br, 3H), 9.94 (s, 1H), 10.49 (s, 1H). MS (ES+): m/z 540 (M+H)+.
EXAMPLE 189. N2-(4-(1H-Pyrazol-1-yl)pheny1)-/V4-(3-tert-butylpheny1)-5-methylpyrimidine-2,4-diamine (Compound CXXX) "N
N
CXXX
[0382] A mixture of intermediate 41 (580 mg, 2.1 mmol) and 4-(1H-pyrazol-1-yl)benzenamine (335 mg, 2.1 mmol) were suspended in acetic acid (10 mL) and heated at 100 C for 4 h. The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure. The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (31 mg, 4%) as a yellow solid.
[0383] 1H NMR (500 MHz, DMSO-d6): 8 1.24 (s, 911), 2.18 (s, 3H), 6.53 (t, J= 2.0 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 7.38 (t, J= 7.9 Hz, 1H), 7.44 (s, 1H), 7.47 (d, J= 8.2 Hz, 111), 7.50 (d, J- 8.9 Hz, 2H), 7.67 (d, J= 8.9 Hz, 2H), 7.73 (s, 1H), 7.95 (s, 1H), 8.43 (d, J= 2.4 Hz, 1H), 9.81 (hr s, 1H), 10.67 (s, 111). MS (ES+): m/z 399 (M+H) .
EXAMPLE 190. M-(7-Chloro-1H-indol-4-y1)-5-methyl-N2-(4-((piperazin-1-yl)methyl)pheny1)-pyrimidine-2,4-diamine (Compound CXXXI) HN
CI
"Nii 1\1.
N LNH
CXXXI
[0384] A mixture of intermediate 40 (150 mg, 0.37 mmol), 4-bromo-7-chloro-1H-indole (87 mg, 0.37 mmol), Pd2(dba)3 (38 mg, 0.04 mmol), Xantphos (76 mg, 0.12 mmol) and cesium carbonate (521 mg, 1.6 mmol) were suspended in dioxane (50 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in CH2C12 (10 mL) and trifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 h at room temperature before 10% NaOH
was added. The organic layer was separated and aqueous was extracted with CH2C12 (10 mL
x 2). The combined organic layers were dried (Na2SO4). The solvent was removed in vacuo.
The residue was purified by HPLC to afford the title compound (26 mg, 15%) as a white solid.
[0385] 1H NMR (500 MHz, DMSO-d6): 5 2.21 (s, 3H), 3.30 (br, 4H), 3.50 (br, 4H), 4.42 (br, 2H), 6.91 (s, 1H), 7.11 (d, J= 8.3 Hz, 1H), 7.40 (d, J= 7.5 Hz, 1H), 7.42 (t, J= 2.7 Hz, 1H), 7.70 (br, 4H), 8.03 (s, 1H), 9.87 (br, 1H), 9.95 (s, 1H), 10.64 (s, 1H), 11.64 (s, 1H). MS
(ES+): m/z 448 (M+H)+.
EXAMPLE 191. A1443-tert-Butylpheny1)-5-methyl-N2-(4-(2-methyl-1H-imidazol-1-ybphenv1)-pyrirnidine-2,4-diamine (Compound CXXXII) N
N
CXXXII
[0386] A mixture of intetinediate 41 (180 mg, 0.65 mmol) and 4-(2-methy1-1H-imidazol-1-yl)benzenamine (113 mg, 0.65 mmol), Pd2(dba)3 (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate (782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (78 mg of HC1 salt, 27%) as a white solid.
[0387] 1H NMR (500 MHz, DMSO-d6): 5 1.26 (s, 9H), 2.21 (s, 3H), 2.50 (s, 3H), 7.31-7.36 (m, 1H), 7.40 (t, J= 7.8 Hz, 1H), 7.44 (d, J= 8.9 Hz, 2H), 7.47 (d, 8.0 Hz, 2H), 7.65 (d, J= 8.9 Hz, 2H), 7.75 (d, J= 2.1 Hz, 1H), 7.79 (d, J= 2.1 Hz, 2H), 8.03 (s, 1H), 10.02 (s, 1H), 11.26 (s, 1H). MS (ES+): m/z 413 (M+H)+.
EXAMPLE 192. 4-(4-Methyl-1H-imidazol4-yl)benzenamine (Intermediate 62) N
[0388] To a solution of 1-fluoro-4-nitrobenzene (1.7 g, 12 mmol) in DMF
(100 mL) was added 4-methyl-1H-imidazole (0.82 g, 10 nunol) and K2CO3 (11g, 80 mmol). The mixture was heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in EtOAc (100 mL) and washed with brine (100 mL x 2). The organic layer was dried and concentrated. The solid was dissolved in Me0H and bubbled with Ar for 2 min. before adding 10% Pd-C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacuo to afford title compound (1.5 g, 87%) as brown solid.
EXAMPLE 193. /V4-(3-tert-Butylpheny1)-5-methyl-N2-(4-(4-methyl-1H-imidazol-1-yl)phenyl) pyrimidine-2,4-diamine (Compound CXXAIII) la NH
(1r I
N
CXXXIII
[0389] A mixture of intennediate 41 (318 mg, 1.15 mmol) and intermediate 62 (200 mg, 1.15 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacua. The residue was purified by HPLC to afford the title compound (66 mg of HC1 salt, 20%) as a white solid.
[0390] 1H NMR (500 MHz, DMSO-d6): 6 1.26 (s, 9H), 2.19 (s, 3H), 2.36 (s, 3H), 7.30 (d, J= 7.9 Hz, 114), 7.41 (d, J= 7.9 Hz, 1H), 7.44 (t, J= 1.8 Hz, 1H), 7.54 (d, J=
7.9 Hz, 1H), 7.59 (d, J= 9.0 Hz, 2H), 7.68 (d, J= 9.0 Hz, 2H), 7.94 (s, 1H), 7.99 (s, 1H), 9.53 (d, J= 1.3 Hz, 1H), 9.72 (br s, 1H), 10.81(br s, 1H). MS (ES+): in/z 413 (M+H)+.
EXAMPLE 194. tert-Butyl 4-(4-aminophenyl)piperidine-1-earboxylate (Intermediate .3_1 NBoc [0391] To a solution of 4-(4-nitrophenyl)piperidine (412 mg, 2 mmol) in CH2C12 (100 mL) was added di-tert-butyl carbonate (480 mg, 2.2 mmol) and N,N-dimethylpyridin-4-amine (50 mg, 0.4 mmol). The mixture was stirred for 20 h at room temperature.
The mixture was added saturated NaHCO3 (100 mL). The organic layer was separated and aqueous was extracted with CH2C12 (50 mL x 2). The combined organic solution was dried and concentrated in vacuo. The residue was dissolved in Me0H and bubbled with Ar for 2 mm. before adding 10% Pd-C. The hydrogenation was finished in 4 h. The catalyst was removed by filtration and solvent was removed in vacua to afford title compound (460 mg, 83%) as white solid.
EXAMPLE 195. /V4-(3-tert-Butylpheny1)-5-methyl-N244-(piperidin-4-y1)phenyl)pyrimidine-2,4-diamMe (Compound CXXXIV) NH NH
S
N
CXXXIV
[0392] A mixture of intermediate 41 (170 mg, 0.6 mmol) and intermediate 63 (170 mg, 0.6 mmol) were suspended in acetic acid (10 mL) and heated at 100 C for 4 h.
The mixture was allowed to cool to room temperature and acetic acid removed under reduced pressure.
The residue was taken in water (20 mL) and neutralized to pH-7. The resulting solution was extracted with Et0Ac (30 mL) and the organic layer separated. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and the crude product purified by HPLC to afford the title compound (8 mg, 3%) as a white solid.
[03931 NMR (500 MHz, DMSO-d6): 6 1.26 (s, 9H), 1.76-1.88 (m, 4H), 2.17 (s, 3H), 2.76-2.81 (m, 1H), 2.93-3.00 (m, 2H), 3.36-3.40 (m, 2H), 7.07 (d, J= 8.5 Hz, 1H), 7.30-7.36 (m, 4H), 7.44 (s, 1H), 7.46 (d, J= 8.7 Hz, 1H), 7.91 (s, 1H), 8.84 (br s, 1H), 8.92 (br s, 1H), 9.73 (s, 1H), 10.45 (s, 1H). MS (ES+): nilz 416 (M+H)+.
EXAMPLE 196. N4-(3-tert-Butylphenv1)-5-methyl-N2-(4-(1-morpholinoethyl)phenyl)pyrhnidine-2,4-diamine (Compound CXXXV1 N N') CXXXV
[0394] A mixture of intermediate 41 (276 mg, 1.0 mmol) and 4-(1-morpholinoethyl)benzenamine (210 mg, 1.0 mmol), Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux under the argon atmosphere for 20 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by HPLC to afford the title compound (17 mg of HC1 salt, 4%) as a yellow solid.
[0395] 114 NMR (500 MHz, DMSO-d6): 6 1.26 (s, 9H), 1.66 (d, J= 6.8 Hz, 3H), 2.19 (s, 3H), 2.79 (br, 2H), 2.92 (br, 1H), 3.61-3.64 (m, 2H), 3.77-3.82 (m, 2H), 3.94-3.99 (m, 2H), 7.32 (d, J = 7.8 Hz, 1H), 7.42 (t, J= 1.9 Hz, 1H), 7.43 (d, J= 7.8 Hz, 1H), 7.46-7.52 (m, 5H), 7.97 (s, 1H), 9.86 (s, 1H), 10.78 (s, 1H), 11.72(br s, 1H). MS (ES+): ni/z 446 (M+H)+.
EXAMPLE 197. 5-Bromo-2-methyl-benzenesulfonyl chloride (Intermediate 64) CI, la Br 0"0 [0396] Bromide (1.99 g, 11.61 mmol) was stirred vigorously and treated with chlorosulfonic acid (1.55 mL, 23.22 mmol). Once addition was complete, resulting red syrup was heated to 60 C. Reaction TLC after 10 min showed no starting material and reaction was quenched by pouring onto ice. Product was extracted by washing with Et0Ac (2 x 150 mL). Organic phase dried over Na2SO4, filtered and evaporated to yellow oil (2.2g, 70%).
EXAMPLE 198. 5-Bromo-2,N-dimethy1-benzenesu1fonamide (Intermediate 65) NH, Br 0/ \O
[0397] A stirring suspension of intermediate 64 (0.43 g, 1.58 mmol) in DCM (5 mL) was treated with 2.0M methylamine solition in THF (2.4 mL, 4.8 mmol). After 16 h reaction solvents were removed and resulting residue diluted with Et0Ac (150 mL) and washed with water. Organic phase dried over Na2SO4, filtered and evaporated to white solids (0.37 g, 89%).
EXAMPLE 199. 2,N-Dimethy1-545-methyl-244-(2-pyrrolidin-1-yl-ethoxy)-pheny1amino1-pyrimidin-4-y1aminol-benzenesu1fonamide (Compound CXXXVI) NH, 4101 \ NH
0"0 oNo N N
CXXXVI
[0398] A mixture of intermediate 65 (0.14 g, 0.52 mmol), intermediate 38 (0.14 g, 0.43 mmol), Pd2(dba)3 (0.040 g, 0.043 mmol), Xantphos (0.050 g, 0.087 mmol) and cesium carbonate (0.43 g, 1.3 mmol) were suspended in dioxane (10 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 15 min. The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.052 g, 24%).
[0399] NMR
(500 MHz, DMSO-d6): 8 1.66-1.70 (m, 4H), 2.08 (s, 3H), 2.43 (d, J = 4.9 Hz, 3H), 2.5 (br s, 4H), 2.78, (t, J= 5.7 Hz), 4.00 (t, J= 5.9 Hz), 6.79 (d, J= 9.0 Hz, 2H), 7.31 (d, J= 9.7 Hz, 1H), 7.42 (q, J= 9.8 Hz, 1H), 7.49 (d, J= 9.0 Hz, 1H), 7.87 (s, 1H), 7.97 (d, J= 2.3 Hz, 1H), 8.07-8.09 (m, 1H), 8.49 (s, 1H), 8.75 (s, 1H). MS (ES+):
ni/z 497 (M+H)+.
EXAMPLE 200. 5-Bromo-N-tert-butyl-2-methyl-benzenesulfonamide ( Intermediate .1 Br \O
[04001 A stirring suspension of intermediate 64 (1.22 g, 4.5 mmol) in DCM (25 mL) was treated with tert-butylamine (1.4 mL, 13.6 mmol). After 16 h, reaction solvents were removed and resulting solids triturated with water. Solids were dried uner vacuum overnight (1.3 g, 94%).
EXAMPLE 201. N-tert-Butv1-542-ehloro-5-methyl-pyrimidin-4-ylamino)-2-methyl-benzenesulfonamide (Intermediate 67) H
Ns NH
0"0 CI
[04011 A
mixture of intermediate 66 (0.90 g, 2.96 mmol), 2-chloro-5-methyl-pyrimidin-4-ylamine (0.33 g, 2.28 mmol), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.264 g, 0.46 mmol) and cesium carbonate (2.2 g, 6.8 mmol) were suspended in dioxane (15 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 15 min.
The reaction mixture was cooled to room temperature and centrifuged down. The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified on silica gel column to afford the title compound as a white solid (0.12 g, 14%).
EXAMPLE 202 N-tert-Buty1-5-12-(4-imidazol-1-yl-phenylamino)-5-methyl-pyrimidin-ylamino1-2-methyl-benzenesulfonamide (Compound CXXXVII) NH N
N N
cxxxva [0402] A mixture of intermediate 67 (0.113 g, 0.31 mmol), 4-imidazol-1-yl-phenylamine (0.059 g, 0.37 mmol), Pd2(dba)3 (0.028 g, 0.03 mmol), Xantphos (0.036 g, 0.06 mmol)- and cesium carbonate (0.3 g, 0.92 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 15 min.
The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.052 g, 24%).
[0403] 1H NMR (500 MHz, DMSO-d6): 5 1.11 (s, 9H), 2.13 (s, 3H), 2.58 (s, 3H), 7.07 (s, 1H), 7.34 (d, J= 8.5 Hz, 1H), 7.42 (d, J= 8.9 Hz, 2H), 7.48 (s, 1H), 7.60 (s, 1H), 7.78 (d, J=
8.9 Hz, 2H), 7.94 (s, 1H), 7.98-8.00 (m, 1H), 8.09 (s, 1H), 8.12 (d, J = 2.3 Hz, 1H), 8.56 (s, 1H), 9.16 (s, 1H). MS (ES+): m/z 492 (M+H)+.
EXAMPLE 203. N-tert-Butv1-3-{5-methy1-244-(pyrrolidine-1-carbony1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXXVIII) /S, NH 0 0"0 40N N LI
CXXXVIII
[0404] A mixture of intatinediate 33 (0.11 g, 0.32 mmol), (4-amino-pheny1)-pyrrolidin-1-yl-methanone (0.072 g, 0.38 mmol), Pd2(dba)3 (0.029 g, 0.032 mmol), Xantphos (0.037 g, 0.063 mmol) and cesium carbonate (0.3 g, 0.95 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C
for 15 min.
The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.040 g, 25%).
[0405] 1H NMR (500 MHz, DMSO-d6): 5 1.11 (s, 9H), 1.8 (br s, 4H), 2.14 (s, 3H), 3.44 (t, J = 6.6 Hz, 4H), 7.38 (d, J = 9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56 (s, 1H), 7.70 (d, J = 9.8 Hz, 2H), 7.98 (s, 1H), 8.08-8.10 (m, 2H), 8.60 (br s, 1H), 9.24 (s, 1H). MS (ES+):
in/z 509 (M+H)+.
EXAMPLE 204. N-tert-Buty1-3-45-methyl-2-14-(morpholine-4-carbony1)-phenylamino1-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXXXIX) H
__.N SS
N
CXXXIX
[0406] A mixture of intermediate 33 (0.13 g, 0.37 mmol), (4-amino-pheny1)-morpholin-4-yl-methanone (0.092 g, 0.45 mmol), Pd2(dba)3 (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075 mmol) and cesium carbonate (0.37 g, 1.1 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C
for 15 min.
The reaction was decanted and the organic phase concentrated in vacuo. The residue was purified by HPLC to afford the title compound as a white solid (0.065 g, 33%).
[0407] NMR (500 MHz, DMSO-d6): 8 1.11 (s, 9H), 2.14 (s, 3H), 3.49 (br s, 4H), 3.59 (br s, 4H), 5.75 (s, 1H), 7.25 (d, J= 9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56 (s, 1H), 7.71 (d, J-9.0 Hz, 2H), 7.98 (s, 1H), 8.06-8.08 (m, 2H), 8.65 (br s, 1H), 9.26 (s, 1H).
MS (ES+): nilz 525 (M+H)+.
EXAMPLE 205. N-tert-Buty1-345-methy1-2-1-4-(piperazine-1-carbony1)-phenylaminol-pyrimidin-4-ylaminol-benzenesulfonamide (Compound CXL) H
N
NN L,NH
CXL
[0408] A mixture of intetinediate 33 (0.12 g, 0.33 mmol), 4-(4-amino-benzoy1)-piperazine-1-carboxylic acid tert-butyl ester (0.12 g, 0.45 mmol), Pd2(dba)3 (0.030 g, 0.037 mmol), Xantphos (0.038 g, 0.075 mmol) and cesium carbonate (0.33 g, 1.1 mmol) were suspended in dioxane (6 mL), sealed in a microwave reaction tube and irradiated with microwaves at 160 C for 15 min. The reaction was decanted and the organic phase concentrated in vacua The residue was purified by silica gel chromatography (25%400%
EtOAc in Hexanes). Product was then treated with 20 mL of 20% TFA solution in DCM.
Solvents then removed by rotary evaporation. Resulting material purified by HPLC to afford the title compound as a white solid (0.045 g, 26%).
[0409] 1H
NMR (500 MHz, DMSO-d6): 5 1.11 (s, 9H), 2.14 (s, 3H), 2.82 (br s, 4H), 3.48 (br s, 4H), 7.24 (d, J= 9.0 Hz, 2H), 7.51-7.53 (m, 2H), 7.55 (s, 1H), 7.71 (d, J= 9.0 Hz, 2H), 7.94 (s, 1H), 8.06-8.08 (m, 2H), 8.65 (br s, 1H), 9.25 (s, 1H). MS (ES+): m/z 524 (M+H)+.
EXAMPLE 206. tert-Butyl 4-(4-(443-methoxyphenylamino)-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-earboxylate (Intermediate 68) O NH
\
I lej NBoc N
[0410] A mixture of 1-bromo-3-methoxybenzene (69.5 pL, 0.56 mmol), intermediate 42 (205 mg, 0.51 mmol), Pd2(dba)3 (23 mg, 0.03 mmol), Xantphos (33 mg, 0.06 mmol) and cesium carbonate (359 mg, 1.10 mmol) in dioxane (3 mL) was irradiated in the microwave at 160 C for 20 min. The reaction mixture was cooled to room temperature, filtered and the filtrate rinsed with DCM and Me0H. The combined liquids were concentrated in vacuo, and .purified using gradient flash chromatography (0-100% ethyl acetate in hexanes) to afford the title compound as a beige solid (215 mg, 83%).
EXAMPLE 207. 3-(2-(4-(Piperidin-4-yloxy)phenylamino)-5-methylpyrimidin-4-ylamino)phenol (Compound CXLI) HO NH
I NH
N
CXLI
[0411] To a mixture of intermediate 68 (215 mg, 0.42 mmol) in DCM (4 mL) was added BBr3 (120 p,L, 1.27 mmol) and stirred at room temperature for 64h. The reaction was quenched with Me0H and concentrated in vacuo. The residue was purified by preparative HPLC and the fractions concentrated in vacuo to afford the TFA salt of the title compound (116 mg, 56%). The TFA salt was taken up in Me0H and passed through SPE PL-MP-Resin cartridges, concentrated in vacuo, triturated with ether, and filtered to provide the title compound as a white solid (31 mg, 69% recovery).
[0412] NMR (500 MHz, DMSO-d6): 8 1.51-1.60 (m, 2H), 1.90-1.98 (m, 2H), 2.07 (s, 3H), 2.70-2.78 (m, 2H), 3.02-3.09 (in, 2H), 4.28-4.36 (m, 1H), 6.48 (dd, J=
8.1, 2.2 Hz ,1H), 6.79 (d, J = 9.1 Hz, 2H), 7.06-7.11 (m, 2H), 7.16 (d, J= 8.5 Hz, 1H), 7.57 (d, J- 9.1 Hz, 2H), 7.82 (s, 1H), 8.08 (s, 1H), 8.73 (s, 1H), 9.27 (br s, 1H). MS (ES+): intz 392 (M+H)+.
EXAMPLE 208. (2-Chloro-5-methyl-pyrimidin-4-y1)-(4-fluoro-3-methoxy-pheny1)-amine (Intermediate 69) '10 SI NH
N
I
CI
[0413] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.2 g, 8.1 mmol), 4-bromo-1-fluoro-2-methoxy-benzene (1.8 g, 8.9 mmol), Pd2(dba)3 (0.74 g, 0.81 mmol), Xantphos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g, 24.2 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on silica gel to afford the title compound (0.3 g, 14%) as a beige solid.
EXAMPLE 209. N4-(4-Fluoro-3-methoxy-pheny1)-5-methyl-N2-14-(2-pyrrolidin-1-0-ethoxy)-phenyli-pyrimidine-2,4-diamine (Compound CXLII) --N- N
CXLII
[0414] A mixture of intelinediate 69 (0.1 g, 0.37 mmol) and 4-(2-pyrrolidin-1-y1-ethoxy)-phenylamine (0.16 g, 0.75 mmol) were suspended in acetic acid (10 mL) and heated to 110 C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.03 g, 17%) as green solids. Ili NMR (500 MHz, DMSO-d6): 8 1.88 (br s, 2H), 2.0 (br s, 2H), 2.15 (s, 3H), 3.08 (br s, 2H), 3.55 (br s, 4H), 3.7 (s, 3H), 4.32 (br s, 2H), 6.9 (d, J= 7.9 Hz, 2H), 7.13 (br s, 1H), 7.21-7.25 (in, 1H), 7.32-7.34 (m, 3H), 7.89 (s, 1H), 9.78 (br s, 1H), 10.48 (br s, 1H), 10.92 (br s, 1H). MS (ES+): m/z 438 (M+H)+.
EXAMPLE 210. (2-Chloro-pyrimidin-4-y1)-(3-methoxy-2-methyl-phenyl)-amine (Intermediate 70) N
I
CI
[0415] A mixture of 3-methoxy-2-methyl-phenylamine (0.68 g, 5 mmol) and 2,4-dichloro-pyrimidine (0.74 g, 5 mmol) were suspended in ethyl alcohol (10 mL) and stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (50 mL), filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.085 g, 7%) as yellow solids.
EXAMPLE 211. N4-(3-Methoxy-2-methyl-phenyl)-N2-[4-(2-pyrrolidin-1-yl-ethoxv)-pheny11-pyrimidine-2,4-diamine (Compound CXLIII) O NH
N (INNO
CXLIII
[0416] A mixture of intermediate 70 (0.08 g, 0.32 mmol) and 4-(2-pyrrolidin-l-yl-ethoxy)-phenylamine (0.13 g, 0.64 mmol) were suspended in acetic acid (10 mL) and heated to 80 C for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by HPLC to afford the title compound (0.03 g, 17%) as grey solids.
[0417] IFINMR (500 MHz, DMSO-d6): 8 1.89 (br s, 2H), 2.0 (br s, 4H), 3.08 (br s, 2H), 3.4 (br s, 4H), 3.54 (br s, 4H), 3.83 (s, 3H), 4.31 (br s, 2H), 6.86 (br s, 2H), 6.97 (d, J= 8.1 Hz, 2H), 7.26 (t, J= 8.1 Hz 1H), 7.34 (br s, 2H), 7.89 (s, 1H), 9.73 (br s, 1H), 10.62 (br s, 2H), 11.01 (br s, 1H). MS (ES+): tn/z 420 (M+H)+. =
EXAMPLE 212. 4-(4-Acetylamino-benzenesulfony1)-piperidine-1-carboxylic acid tert-butvl ester (Intermediate 711 0 õP
0 fel s N N
[0418] A mixture of 4-(4-bromo-benzenesulfony1)-piperidine-1-carboxylic acid tert-butyl ester (4 g, 9.92 mmol), acetamide (0.88 g, 14.9 mmol), Pd2(dba)3 (0.46 g, 0.49 mmol), Xantphos (0.56 g, 0.99 mmol) and cesium carbonate (9.7 g, 29.8 mmol) were suspended in dioxane (60 mL) and heated at reflux under the argon atmosphere for 4 h. The reaction mixture was cooled to room temperature and poured onto ice. Resulting yellow solids collected by filtration and dried. Crude product was purified by flash chromatography on silica gel to afford the title compound as a beige solid (3.12 g, 82%).
EXAMPLE 213. 4-(4-Amino-benzenesulfonyI)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 72) 0õp N
H
[0419] A suspension of intermediate 71 (2.6 g, 6.7 mmol) was diluted with 60 mL of Claisen's alkali (88 g KOH dissolved in 63 mL H20 diluted up to 250 mL with Me0H) and heated to 90 C. After 2 h, reaction was removed from heating, cooled to room temperature and diluted with water (50 mL). Grey solids collected by suction filtration, washed with water and dried overnight (2.2 g, 97%).
EXAMPLE 214. N4-(4.-Ch1oro-3-methoxy-pheny1)-5-methy1-N2-14-(piperidine-4-sulfony1)-phenyll-pyrimidine-2,4-diamine (Compound CXLIV).
Cl NH 0\ ,0 (110 =N
-N N H
CXLIV
[0420] A mixture of inten-nediate 31 (0.14 g, 0.51 mmol), intermediate 72 (0.19 g, 0.56 mmol), Pd2(dba)3 (0.046 g, 0.051 rnmol), Xantphos (0.59 g, 0.1 mmol) and cesium carbonate (0.5 g, 1.52 mmol) were suspended in dioxane (8 inL) and microwaved at 160 C
for 15 min.
The reaction mixture was cooled to room temperature and centrifuged down.
Solvents were then decanted and evaporated. Resulting residue was purified by flash chromatography on silica gel to afford the N-protected precursor of title compound. These solids were treated with 20% TFA in DCM solution and immediately evaporated. Residue was dissolved in minimum amount to Et0Ac and added dropwise to large excess of diethyl ether.
Resulting light yellow powder was collected by filtration and dried (0.16 g, 55%).
[0421] 1H NMR (500 MHz, DMSO-d6): 1.61-1.69 (m, 2H), 1.98-2.01 (m, 2H), 2.16 (s, 3H), 2.86 (q, J= 12 Hz, 2H), 3.35 (d, J= 12.6 Hz, 2H), 3.64 (tt, J= 11.7 Hz, J= 3.8 Hz, 1H), 3.79 (s, 3H), 7.34 (dd, J= 8.7 Hz, J= 2.0 Hz, 1H), 7.39-7.41 (m, 2H), 7.6 (d, J= 8.9 Hz, 2H), 7.91 (d, J= 8.9 Hz, 2H), 8.02 (s, 1H), 8.19-8.21 (m, 1H), 8.6-8.63 (m, 1H), 8.89 (br s, 1H). MS (ES+): m/z 488 (M+H)+.
EXAMPLE 215. (4-Chloro-3-methyl-pheny1)-(2-ehloro-5-methyl-pyrimidin-4-y1)-amine (Intermediate 73) Cl NH
N CI
[0422] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol), bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8 '1), Pd2(dba)3 (0.21 g, 0.23 mmol), Xantphos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g, 7 mmol) were suspended in dioxane (9 mL) microwaved at 160 C for 20 mm. The reaction mixture was cooled to room temperature and centrifuged down. Solvents were then decanted and evaporated.
Resulting residue was purified by flash chromatography on silica gel to afford title compound as yellow solids (0.24 g, 38%).
EXAMPLE 216. /V4-(4-Chloro-3-methyl-pheny1)-5-methyl-N2-[4-(piperidin-4-yloxy)-pheny11-pyrimidine-2,4-diamine (Compound CXLV) CI
NH
N (j NH
-N N
CXLV
[0423] A mixture of intermediate 73 (0.071 g, 0.27 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) were diluted with HOAc (5 mL) and microwaved at 150 C for 15 mm. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.025 g, 22%).
[0424] IHNMR (500 MHz, DMSO-d6): 6 1.76-1.83 (m, 2H), 2.05-2.09 (in, 2H), 2.13 (s, 3H), 2.27 (s, 3H), 3.10 (br s, 2H), 3.16 (br s, 2H), 4.58-4.61 (m, 1H), 6.93 (d, J= 9 Hz, 2H), 7.34-7.39 (m, 3H), 7.43-7.45 (m, 1H), 7.59 (s, 1H), 7.87 (s, 1H), 8.51 (br s, 1H), 8.55 (br s, 1H), 9.38 (br s, 1H), 10.0 (br s, 1H). MS (ES+): mlz 424 (M+H)+.
EXAMPLE 217. N-(3-Bromo-phenyl)-acetamide (Intermediate 74) Br [0425] A solution of 3-bromo-phenylamine (1.04 g, 6 mmol) was treated with DIEA (2.3 mL, 13.3 mmol) and chilled to zero degrees. Acetyl chloride (0.47 mL, 6.7 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to beige solids (1.25 g, 98%).
EXAMPLE 218. N43-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-phenyll-acetamide (Intermediate 75) N CI
NH
[0426] A mixture of 2-ch1oro-5-methyl-pyrimidin-4-ylamine (0.71 g, 4.9 mmol), intermediate 74 (1.25 g, 5.9 mmol), Pd2(dba)3 (0.45 g, 0.49 mmol), Xantphos (0.57 g, 0.98 mmol) and cesium carbonate (4.8 g, 14.7 mmol) were suspended in dioxane (40 mL) refluxed for 18 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.44, 32%).
EXAMPLE 219. N-(3-15-Methy1-2-[4-(piperidin-4-vloxy)-phenylaminol-pyrimidin-4-ylaminol-pheny1)-acetamide (Compound CXLVI) )Lo NH
N-7N1\1 o'"----N1 NH
N N
H
CXLVI
[0427] A mixture of intermediate 75 (0.074 g, 0.27 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.35 mmol) were diluted with HOAc (5 mL) and microwaved at 150 C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.072 g, 62%).
[0428] 1H NMR (500 MHz, DMSO-d6): 8 1.74-1.81 (m, 2H), 2.03-2.07 (m, 5H), 2.15 (s, 3H), 3.09 (br s, 2H), 3.24 (br s, 2H), 4.54-4.57 (m, 1H), 6.85 (d, J- 8.8 Hz, 2H), 7.22 (d, J =
7.7 Hz, 2H), 7.29-7.39 (m, 4H), 7.77 (s, 1H), 7.87 (s, 1H), 8.55 (br s, .1H), 8.60 (br s, 1H), 9.67 (s, 1H), 10.0 (br s, 111), 10.2 (br s, 1H). MS (ES+): nilz 433 (M+H)+.
EXAMPLE 220. N-(3-Bromo-2-methyl-phenyl)-acetamide (Intermediate 76) Br [0429] A solution of 3-bromo-2-methyl-phenylamine (4.1 g, 21.9 mmol) was treated with DIEA (8.4 mL, 48 mmol) and chilled to zero degrees. Acetyl chloride (1.7 mL, 24.1 mmol) was added dropwise via syringe. Reaction was allowed to return to room temperature and stir for 1 hour. Reaction was then poured onto water and washed once. Organic phase was evaporated to off-white solids. Trituration with hexanes afforded title compound as white solids (4.4 g, 89%).
EXAMPLE 221. N-13-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-2-methyl-phenyll-acetamide (Intermediate 77) NH
N CI
[0430] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.86 g, 5.9 mmol), intermediate 76 (1.6 g, 7.1 mmol), Pd2(dba)3 (0.55 g, 0.59 mmol), Xantphos (0.69 g, 1.2 mmol) and cesium carbonate (5.8 g, 17.8 mmol) were suspended in dioxane (40 mL) refluxed for 16 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated. Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.56 g, 32%).
EXAMPLE 222. N-(2-Methyl-3-15-methyl-2-14-(piperidin-4-yloxy)-phenylaminol-PYrimidin-4-ylaminol-phenyl)-acetamide (Compound CXLVII)
16 NH
-%1\1 IC)L1 =-N)N.N
CXL VII
[0431] A mixture of intermediate 77 (0.15 g, 0.5 mmol) and 4-(4-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.65 mmol) were diluted with HOAc (5 mL) and microwaved at 150 C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.091 g, 41%).
[0432] NMR (500 MHz, DMSO-d6): 8 1.71-1.78 (m, 2H), 2.02-2.08 (m, 8H), 2.16 (s, 3H), 3.09 (br s, 2H), 3.24 (br s, 2H), 4.50-4.52 (m, 1H), 6.77 (d, J= 8.4 Hz, 2H), 7.09-7.15 (m, 3H), 7.27 (t, J= 7.9 Hz, 1H), 7.49 (d, J= 8.1 Hz, 1H), 7.86 (s, 1H), 8.54 (br s, 1H), 8.59 (br s, 1H), 9.45 (s, 1H), 9.84 (br s, 1H), 10.34 (br s, 1H). MS (ES+): in/z 447 (M+H)+.
EXAMPLE 223. 5-Methyl-N2-[4-(4-methyl-piperazin-l-y1)-phenyl]-N4-(3-nitro-phenyl)-pyrimidine-2,4-diamine (Intermediate 78) =
v211 NH N-N') N
[0433] A mixture of 1-bromo-3-nitro-benzene (0.77 g, 3.8 mmol), intermediate 32 (0.95 g, 3.2 mmol), Pd2(dba)3 (0.29 g, 0.32 mmol), Xantphos (0.37 g, 0.64 mmol) and cesium carbonate (3.1 g, 9.6 mmol) were suspended in dioxane (40 mL) refluxed for 16 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated.
Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.53 g, 40%).
EXAMPLE 224. 1V4-(3-Amino-phenyl)-5-methyl-N2- 4-(4-methyl-piperazin-1-14)-phenyl]-pyrimidine-2,4-diamine (Intermediate 79) L-1\1 410 N) N N
[0434] Slurry of intermediate 78 (0.23 g, 0.54 mmol) in Me0H (25 mL) was purged with argon and treated with Pd/C 10% wt. (0.18 g). Reaction atmosphere was replaced with hydrogen and stirred for 4 h. Hydrogen balloon was then removed and argon was flushed through reaction before filtration through Celite. Solvents were then evaporated to pale brown solids (0.17 g, 83%).
EXAMPLE 225. 1-(345-Methy1-2-14-(4-methyl-piperazin-l-y1)-phenylaminol-pyrimidin-4-ylaminol-pheny1)-3-phenyl-urea (Compound CXLVIII) ei ei N N NH r'NN
H H
40, N'`) N N
CXLVIII
[0435] A suspension of intermediate 79 (0.17 g, 0.45 mmol) in DCM (10 mL) was treated with phenyl isocyanate (0.058 mL, 0.54 mmol) and stirred for 1 hour. Reaction solvents then removed and resulting residue purified by HPLC to provide title compound as white solids (0.075 g, 33%).
[0436] 114 NMR (500 MHz, DMSO-d6): 6 2.09 (s, 3H), 2.15 (s, 3H), 2.30-2.32 (m, 4H), 2.92-2.94 (m, 4H), 6.74 (d, J¨ 8.4 Hz, 2H), 6.94-6.97 (m, 1H), 7.19-7.28 (m, 5H), 7.45 (d, J
8.8 Hz, 2H), 7.53 (d, J= 9.0 Hz, 2H), 7.73 (br s, 1H), 7.83 (s, 1H), 8.23 (s, 1H), 8.68 (s, 1H), 8.74 (s, 1H), 8.78 (s, 1H). MS (ES+): in/z 509 (M+H)+.
EXAMPLE 226. 143-15-Methy1-2-f444-methyl-piperazin-1-171)-phenylaminol-pyrimidin-4-ylaminol-phenyl)-343-trifluoromethyl-pheny1)-urea (Compound CXLIX) F3 eiN N NH
H H
N INL') N N
CXLIX
[0437] A suspension of intermediate 79 (0.1 g, 0.26 mmol) in DCM (8 mL) was treated with 1-isocyanato-3-trifluorornethyl-benzene (0.043 mL, 0.31 mmol) and stirred for 1 hour.
Reaction solvents then removed and resulting residue purified by HPLC to provide title compound as white solids (0.039 g, 26%).
[0438] 114 NMR (500 MHz, DMSO-d6): 8 2.16 (s, 3H), 2.82 (s, 3H), 2.86 (br s, 2H), 3.08 (br s, 2H), 3.42 (br s, 2H), 3.69 (br s, 2H), 6.88 (d, J= 8.4 Hz, 2H), 7.20 (br s, 1H), 7.29-7.33 (m, 5H), 7.52 (t, J= 7.9 Hz, 1H), 7.57 (d, J= 8.5 Hz, 1H), 7.77 (s, 1H), 7.84 (s, 1H), 8.09 (s, 1H), 9.42 (s, 1H), 9.66 (s, 1H), 9.71 (br s, 1H), 10.1 (br s, 1H). MS (ES+):
777/Z 577 (M+H)+.-EXAMPLE 227. (2-Chloro-5-methyl-pyrimidin-4-y1)-(2-methvi-3-trifluoromethyl-pheny1)-amine (Intermediate 80) =
POI
N CI
[0439] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.18 g, 5.9 mmol), 1-bromo-2-methyl-3-trifluoromethyl-benzene (0.33 g, 1.4 mmol), Pd2(dba)3 (0.12 g, 0.13 mmol), Xantphos (0.15 g, 0.25 mmol) and cesium carbonate (1.23 g, 3.8 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 18 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.095 g, 25%).
EXAMPLE 228. 5-Metirvi-N4-(2-methyl-3-trifluoromethyl-pheny1)-N244-(piperidin-yloxy)-phenyll-pyrirnidine-2,4-diamine (Compound CL) F3c NH
N N NH
CL
[0440] A mixture of intermediate 80 (0.058 g, 0.2 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.073 g, 0.25 mmol) were diluted with HOAc (5 mL) and microwaved at 150 C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.025 g, 30%).
[0441] 1H NMR (500 MHz, DMSO-d6): 8 1.71-1.78 (in, 2H), 2.00-2.04 (m, 2H), 2.18 (s, 3H), 2.25 (s, 3H), 3.08 (br s, 2H), 3.22 (br s, 2H), 4.50-4.52 (m, 1H), 6.70 (d, J= 8.3 Hz, 2H), 7.10 (d, J= 8.9 Hz, 2H), 7.54 (t, J= 7.8, 1H), 7.62 (d, J= 7.7 Hz, 1H), 7.75 (d, J= 7.8 Hz, 1H), 7.91 (s, 1H), 8.54 (br s, 1H), 8.61 (br s, 11-1), 9.88 (s, 1H), 10.34 (br s, 1H). MS
(ES+): ni/z 458 (M+H)+.
EXAMPLE 229. (3-13romo-phenyl)-pyrrolidin-1-yl-rnethanone (Intermediate 81) ON Si Br [0442] A solution of 3-bromo-benzoyl chloride (2.7 g, 12 mmol) in DCM (40 mL) was chilled to zero degrees and treated with pyrrolidine (3 mL, 36.8 mmol).
Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (3.1g, 100%).
EXAMPLE 230. [3-(2-Chloro-5-methyl-pyrimidin-4-ylarnino)-phenyll-pyrrolidin-1-yl-methanone (Intermediate 821 NH
ON
CI
[0443] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.22 g, 1.5 mmol), intermediate 81 (0.46 g, 1.8 mmol), Pd2(dba)3 (0.14 g, 0.15 mmol), Xantphos (0.17 g, 0.3 mmol) and cesium carbonate (1.5 g, 4.5 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 18 min. Reaction vessel was then centrifuged down and decanted.
Solvents then evaporated and resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.25 g, 53%).
EXAMPLE 231. (3-15-Methy1-2-1-4-(piperidin-4-y1oxy)-pheny1amino1-pyrimidin-4-ylarninol-pheny1)-pyrrolidin-1-yl-methanone (Compound CLI) NH
411, ,N*N
CLI
[0444] A mixture of intermediate 82 (0.1 g, 0.32 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) were diluted with HOAc (6 mL) and microwaved at 150 C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.005 g, 3%).
[0445] 1H NMR (500 MHz, DMSO-d6): 8 1.74-1.81 (in, 4H), 1.83-1.88 (in, 2H), 2.05-2.09 (in, 2H), 2.16 (s, 3H), 2.25 (s, 3H), 3.25 (hr s, 2H), 3.34 (t, J= 6.5 Hz, 2H), 3.46 (t, J=
6.9 Hz, 2H), 4.45-4.59 (m, 1H), 6.91 (d, J= 8.8 Hz, 2H), 7.32 (d, J= 8.9 Hz, 2H), 7.36 (d, J
= 7.7 Hz, 1H), 7.43 (t, J= 7.8, 1H), 7.67 (d, J= 7.9 Hz, 1H), 7.70 (s, 1H), 7.89 (s, 1H), 8.50 (hr s, 1H), 8.56 (br s, 1H), 9.64 (hr s, 1H), 10.21 (hr s, 1H). MS (ES+): m/z 473 (M+H)+.
EXAMPLE 232. 3-Bromo-N-isopropyl-benzamide (Intermediate 83) Br [0446] A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 inmol) in DCM (40 mL) was chilled to zero degrees and treated with isopropylamine (0.96 mL, 11.32 mmol).
Reaction was allowed to come to room temperature and stir for 24 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filleted and evaporated to white solids (0.6 g, 66%).
EXAMPLE 233. N-Isopropy1-3-{5-methyl-244-(4-methyl-piperazin-l-y1)-phenylaminol-pyrimidin-4-ylaminol-benzamide (Compound CLII) NH
0 N N'-) N N
CLII
[0447] A mixture of intetinediate 32 (0.1 g, 0.34 mmol), intermediate 83 (0.13 g, 0.54 mmol), Pd2(dba)3 (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067 mmol) and cesium carbonate (0.33 g, 1 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 15 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by HPLC to afford title compound as white solids (0.011 g, 7%).
[0448] NMR (500 MHz, DMSO-d6): 8 1.14 (d, J= 6.7 Hz, 6H), 2.16 (s, 4H), 2.87 (s, 4H), 3.10 (br s, 2H), 3.51 (s, 2H), 4.22 (in, 1H), 6.85 (d, J= 8.8 Hz, 2H), 7.30-7.32 (in, 2H), 7.45 (t, J= 7.8 Hz, 1H), 7.69-7.70 (in, 2H), 7.90 (s, 1H), 7.99 (s, 1H), 8.24 (d, J= 7.7 Hz, 1H), 9.70 (br s, 1H), 9.94 (br s, 1H), 10.2 (br s, 1H). MS (ES+): m/z 460 (M+H)+.
EXAMPLE 234. 3-Bromo-N-tert-butyl-benzamide (Intermediate 84) A.NH
Br [0449] A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (10 mL) was chilled to zero degrees and treated with tert-butylamine (1.2 mL, 11.3 mmol).
Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (0.9 g, 94%).
EXAMPLE 235. N-tert-Buty1-3-{5-methyl-244-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzamide (Compound CLIII) =
N el NH
0 N = N'-) ,1\1 CLIII
[0450] A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 84 (0.1 g, 0.4 mmol), Pd2(dba)3 (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067 mmol) and cesium carbonate (0.33 g, 1 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 15 mm. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by HPLC to afford title compound as white solids (0.055 g, 35%).
[0451] 1H NMR (500 MHz, DMSO-d6): 8 1.36 (s, 9H), 2.09 (s, 31-1), 2.21 (s, 3H), 2.43 (t, J= 2.8 Hz, 4H), 3.00 (t, J= 2.8 Hz, 4H), 6.74 (d, J= 9.1 Hz, 2H), 7.35 (t, J=
7.9 Hz, 1H), 7.44-7.48 (m, 3H), 7.67 (s, 1H), 7.85 (s, 1H), 7.88-7.92 (m, 2H), 8.36 (s, 1H), 8.74 (s, 1H).
MS (ES+): ni/z 474 (M+H)+. =
EXAMPLE 236. 5-Methyl-N244-(4-methyl-piperazin-l-y1)-phenyll-/V4-(3-piperidin-0-pheny1)-pyrimidine-2,4-diatnine (Compound CLIV) HN '1\1 NI') N
CLIV
[0452] A mixture of inteanediate 32 (0.08 g, 0.27 mmol), 4-(3-bromo-phenyl)-piperidine (0.084 g, 0.35 mmol), Pd2(dba)3 (0.025 g, 0.027 mmol), Xantphos (0.031 g, 0.054 mmol) and cesium carbonate (0.26 g, 0.81 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 15 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by HPLC to afford title compound as white solids (0.007 g, 6%).
[0453] IHNMR (500 MHz, DMSO-d6): 6 1.74-1.79 (m, 3H), 2.09 (s, 3H), 2.21 (s, 3H), 2.43 (t, J= 2.8 Hz, 4H), 3.00 (t, J= 2.8 Hz, 4H), 6.76 (d, J= 9.1 Hz, 2H), 6.90 (d, = 7.7 Hz, 1H), 7.24 (t, J= 7.9 Hz, 1H), 7.47-7.53 (m, 3H), 7.68 (d, J= 8.2 Hz, 1H), 7.82.(s, 1H), 8.18 (s, 1H), 8.67 (s, 1H). MS (ES+): in/z 458 (M+H)+.
EXAMPLE 237. 4-(3-{5-Methy1-2-f4-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-y1aminol-benzenesulfony1)-piperidine-1-carboxylic acid benzyl ester (Intermediate 85) 0)N 411) NH rN
00 õ.),, N f\L`) jj.N
[0454] A mixture of intermediate 32 (0.17 g, 0.58 mmol), 4-(3-bromo-benzenesulfony1)-piperidine-1-carboxylic acid benzyl ester (0.28 g, 0.64 mmol), Pd2(dba)3 (0.053 g, 0.058 mmol), Xantphos (0.067 g, 0.12 mmol) and cesium carbonate (0.57 g, 1.74 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 15 min. Reaction vessel was then centrifuged down and decanted onto ice. Yellow solids collected, dried and used without further purification (0.4 g, 100%).
EXAMPLE 238. 5-Methyl-N2-1-4-(4-methyl-piper azin-l-y1)-ph env"! j3-(piperidine-4-sulfony1)- phenyl] pyrimidine-2,4-diamine (Compound CLV1 NH
N i\L`) N N
CLV
[0455] A stirring solution of intermediate 85 (0.17 g, 0.26 mmol) in DCM (15 mL) was treated with 1M BBr3 in DCM (2 mL, 2 mmol). After 4 h, reaction was quenched by slow addition of Me0H (4 mL) followed by removal of solvents. Residue purified by HPLC to provide title compound as purple powder (0.008 g, 6%).
[0456] Ill NMR (500 MHz, DMSO-d6): 8 1.31-1.40 (m, 2H), 1.75 (d, J= 10.8 Hz, 2H), 2.12 (s, 3H), 2.21 (s, 3H), 2.36-2.41 (m, 2H), 2.44 (t, J= 4.9 Hz, 4H), 2.95 (d, J = 12.5 Hz, 2H), 3.02 (t, J- 4.9 Hz, 4H), 3.24 (tt, J= 11.7 Hz, J= 3.8 Hz, 1H), 6.81 (d, J= 9.0 Hz, 2H), 7.44 (m, 3H), 7.56 (t, J= 8.0 Hz, 1H), 7.90-.7.91 (m, 2H), 8.49 (d, J= 7.6 Hz, 1H), 8.60 (s, 1H), 8.74(s, 1H). MS (ES+): m/z 522 (M+H)+.
EXAMPLE 239. tert-Butyl 444-(4-(1H-indo1-4-ylamino)-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-l-carborylate (Intermediate 86) HN
=
NH
() I
N
86 NyO
[04571 A mixture of 4-bromo-1H-indole (41 !AL, 0.33 mmol), intermediate 42 (131 mg, 0.33 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), Xantphos (60 mg, 0.10 mmol) and cesium carbonate (428 mg, 1.31 mmol) in dioxane (3 mL) was irradiated in the microwaved at 160 C for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM. The filtrate was concentrated and purified by gradient flash chromatography (0-15% Me0H in DCM) to afford the title compound as a white solid (30 mg, 17%).
EXAMPLE 240. M-(1H-Indol-4-y1)-5-methyl-N2-(4-(piperidin-4-yloxy)phenyppyrimidine-2,4-diamine (Compound CLVI) HN
()) I
N MP' NH
CLVI
[0458] A mixture of intermediate 86 (27 mg, 0.05 mmol) in 30% TFA/DCM (1 mL) was stirred for 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC. The resulting fractions were concentrated in vacuo to obtain the TFA
salt of the title compound as a tan solid (11 mg, 43%).
[0459] 1H NMR (500 MHz, DMSO-d6): 6 1.71-1.77 (m, 2H), 1.98-2.06 (m, 2H), 2.22 (s, 3H), 3.03-3.12 (m, 2H), 3.19-3.27 (m, 2H), 4.44-4.53 (m, 1H), 6.34-6.37 (m, 1H), 6.64 (br d, J= 8.3 Hz, 2H), 7.08 (t, J= 7.2 Hz, 3H), 7.14 (t, J= 7.8 Hz, 1H), 7.36 (t, J=
2.7 Hz, 1H), 7.39 (d, J= 8.1 Hz, 1H), 7.84 (s, 1H), 8.48 (br s, 1H), 8.55 (br s, 1H), 9.85 (br s, 1H), 9.98 (br s, 1H), 11.27 (s, 1H).
EXAMPLE 241. 2-Chloro-N-12-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-5-01-5 (3-trifluoromethyl-benzoylamino)-benzamide (Compound CL VII) I
-N N
CL VII
[0460] A mixture of 3-bromopyridine (379 mg, 2.4 mmol), 4-amino-2-chloro-5-methylpyrimidine (287 mg, 2.0 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol) and cesium carbonate (975 mg, 3.0 mmol) in dioxane ( 15 mL) was heated under refluxed for 1 h under argon. The solvent was removed and the residue on purification by HPLC gave an intermediate, 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine as yellow solid (252 mg, 57%). For second Buckwald, a mixture of 2-chloro-5-methyl-N-(pyridin-3-yOpyrimidin-4-amine (80 mg, 0.36 mmol), 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (74 mg, 0.34 mmol), Pd2(dba)3 (3.2 mg, 0.003 mmol), xantphos (4.2 mg, 0.007 mmol) and cesium carbonate (234 mg, 0.72 mmol) in dioxane ( 5 mL) was heated under refluxed for 1 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as light brown solid (28 mg, 20%).
[0461] 1H NMR (500 MHz, DMSO-d6): 8 1.85-1.95 (m, 2H), 2.0-2.09 (m, 2H), 2.18 (s, 3H), 3.09-3.18 (m, 2H), 3.55-3.65 (m, 4H), 4.27 (dd, J= 5.2, 4.7 Hz, 2H), 6.94 (d, J= 8.9 Hz, 2H), 7.35 (d, J= 8.9 Hz, 2H), 7.50 (dd, J= 8.2, 4.8 Hz, 1H),7.92-7.96 (m, 1H), 8.08-8.15 (m, 1H), 8.45 (dd, J= 4.8, 1.4, 1H), 8.84, 9.75, 9.85, 10.24 (4 br s, 1H
each). MS (ES+): m/z 329 (M+H)+.
EXAMPLE 242. N2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-5-methyl-M-(3-(trifluoromethoxy)phenyl) pyrimidine-2,4-diamMe (Compound CLVIII) F3C,o NH
00) C)NI\D
N N
CL VIII =
[0462] A mixture of 1-bromo-3-(trifluoromethoxy)benzene (241 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane ( 15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue on purification by HPLC gave an intermediate, 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amineas brown solid (260 mg, 85 %). A mixture of this inteimediate (100 mg, 0.33 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (67 mg, 0.33 mmol) in glacial acetic acid (5 mL) was heated under refluxed for 3 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as white solid (11 mg, 7 %).
[0463] 1H NMR (500 MHz, DMSO-d6): 5 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.51-2.55 (m, 2H, superimposed with solvent peak), 2.75 (t, J= 5.9 Hz, 2H), 3.25-3.34 (m, 2H, superimposed with water peak), 3.99 (t, J= 5.9 Hz, 2H), 6.79 (d, J= 8.9 Hz, 2H), 6.98 (d, 1=
8.0 Hz, 1H), 7.40 (dd, J= 7.6, 7.4 Hz, IH), 7.50 (d, J= 8.9 Hz, 2H), 7.76 (br s, 1H), 7.87 (d, J= 8.4 1H), 7.90, 8.31, 8.41, 8.84 (4 s, 1H each). MS (ES+): in/z 474 (M+H)+.
EXAMPLE 243. N2-(4-(2-(pyrrolidin-1-yflethoxy)pheny1)-N444-ehloro-3-(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine (Compound CLIX) ci N
N N
CLIX
[0464] A mixture of 4-bromo-1-chloro-2-(trifluoromethypbenzene (259 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane ( 15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue was purified by HPLC to give an intermediate 2-chloro-N-(4-chloro-3-(trifluoromethyl) phenyl)-5-methylpyrimidin-4-amine as brown solid (200 mg, 62 %). A mixture of this intetmediate (161 mg, 0.5 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (103 mg, 0.5 mmol) in glacial acetic acid (5 mL) was heated under refluxed for 3 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as brown solid (75 mg, 31 %).
[0465] 1HNMR (500 MHz, DMSO-do): 6 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.51-2.55 (m, 4H, superimposed with solvent peak), 2.75 (t, J= 6.0 Hz, 2H), 4.0 (t, J= 5.9 Hz, 2H), 6.79 (d, J= 8.5 Hz, 2H), 7.47 (d, J= 9.0 Hz, 2H), 7.58 (d, J= 9.0 Hz, 2H), 7.93 (s, 1H), 8.01 (d, J
= 2.5 Hz, 1H), 8.22 (d, J= 8.5 Hz, 2H), 8.60, 8.88 (2 s, 1H each). MS (ES+):
tntz 492 (M+H)+.
EXAMPLE 244. IC50 Value Determinations for Jak2 Kinase [0466] The IC50 values for compounds were determined using a luminescence-based kinase assay with recombinant JAK2 obtained from Upstate Cell Signaling Solutions. In white, fiat-bottom, 96-well plates (Nunc) parallel assays were run at room temperature at a final volume of 50 p,L. Each well contained 40 1_1,L of buffer consisting of 40 mM Tris buffer, pH 7.4, containing 50 mM MgCl2, 800 )1M EGTA, 350 jM Triton X-100, 2 mM
mercaptoethanol, 1001_tM peptide substrate (PDKtide; Upstate Cell Signaling Solutions) and an appropriate amount of JAK2 (75 ¨ 25 ng/well) such that the assay was linear over 60 min.
The final concentrations of TargeGen compounds for IC50 value determinations ranged from 1000 to 0.01 )..LM by adding the appropriate amount of compound in 2.5 111, of DMSO; the DMSO present in each assay was constant at 5%. The reaction was initiated by the addition of 10 tL of ATP to a final assay concentration of 3 1.1M. After the reaction had proceeded for 60 min, 50 ).1,L of Kinase-Glo reagent (Promega) was added to terminate the reaction. This solution was then allowed to proceed for an additional 10 min to maximize the luminescence reaction.
[0467] Values were then measured using an Ultra 384 instrument (Tecan) set for luminosity measurements. Two control reactions were also ran: one reaction containing no compound and the second containing neither inhibitor nor peptide substrate.
IC50 values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4; GraphPad Software). The results are shown in Table 1.
TABLE 1. Compounds of the Invention And Their IC Values for Jak2 Kinase , Structure - Name -0 II NH 4-(2,4-Dichloro-5-methoxy-NC-C)---NO 6240 I 1-yl-ethoxy)-phenylamino]-N N pyrimidine-5-carbonitrile CI 40 ci 4-(2,4-Dichloro-5-methoxy-NH
phenylamino)-2-[3-(2-pyrrolidin-NCj, 10500 N
1-yl-ethoxy)-phenylamino]-N 4111 pyrimidine-5-carbonitrile CI 40 ci N4-(2,4-Dichloro-5-methoxy-NH phenyl)-5-methyl-N2-[3 -(2-Me pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine , Structure Name _ 1. N2-(4-(2-(pyrrolidin-1-'o y1-I yl)ethoxy)pheny1)-N4-(3-N 5 -`N methoxypheny1)-5- 52.8 , methylpyrimidine-2,4-diamine N Hydrochloride H
lel 02N NH N2-(4-(2-(pyrrolidin-1-yl)ethoxy)pheny1)-5-methyl-N4-61.1 1\ N (3-nitrophenyl)pyrimidine-2,4-I ),. diamine Hydrochloride r H
. N4-(4-Methoxy-phenyl)-N244-[4 NH (2-pyrrolidin-1-yl-ethoxy)-)-i N 401 (:)-NLD phenyq-pyrimidine-2,4-diamine NN trifluoroacetate H
0 ei 4-[4-(4-Methoxy-phenylamino)-NH 9 i----\ pyrimidin-2-ylaminc]-N-(2-pyrrolidin-l-y1-ethyl) 10700 1 benzenesulfonamide N N 0 0 H trifluoroacetate H
04-[4-(3-Methoxy-pheny1amino)-9 r--\\ pyrimidin-2-ylaminc]-N-(2-pyrrolidin-l-yl-ethyl)- 638 L'i N .1\1.1\1-/
0 H benzenesulfonamide N N 410 trifluoroacetate <0 40 o NH N4-Benzo[1,3]dioxo1-5-y1-5-methyl-N244,-(2-pyrrolidin-1-yl-N el C)NO 87.2 i ethoxy)-phenyl}-pyrimidine-2,4-N diamine trifluoroacetate H
NH
4-[4-(4-Hydroxy-phenylamino)-9 pyrimidin-2-ylamino]-N-(2-N
)1\1 el .,NN pyrrolidin-l-yl-ethyl)-I o H benzenesulfonamide N
H
Structure Name JAK2 HO NH
3-(2-(4-(2-(pyrrolidin-1-ypethoxy)phenylamino)-5-NLsi N 0 0,--,N9 methylpyrimidin-4-ylarnino)phenol Hydrochloride .-N N
H
HO NH 444-(3-Hydroxy-phenylamino)-II 0 pyrimidin-2-ylaminoi-N-(2-'N N pyrrolidin-l-yl-ethyl)- 3620 N
1 0 H benzenesulfonamide '1\r H trifluoroacetate N N-Methy1-3- {5-methy1-2-{4-(2-NH
pyrrolidin-l-yl-ethoxy)-0 --...õ..--L, N Am 0.õ.....õ----,0 phenylaminoi-pyrimidin-4-ylaminol-benzamide H
C, Op -,0 NH N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N244-(2-7.96 pyrrolidin-l-yl-ethoxy)-phenyll-N N pyrimidine-2,4-diamine H
/ N
I
N2-(4-(2-(pyrrolidin-1-NH
yl)ethoxy)pheny1)-N4-=N N Si IC)'== N\ (isoquinolin-l-y1)-5-i methylpyrimidine-2,4-diamine ' H
NNN I. NH N4-(3-Dimethylamino-phenyl)-5-I methyl-N244-(2-pyrrolidin-1-yl- 19.7 0 (:)------NLD ethoxy)-phenyll-pyrimidine-2,4- .
i diamine 'N N
H
CI NH 4-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-5-N 411 67.5 methylpyrimidin-4-ylamino)-2-I ), -.N.-- N chlorobenzonitrile Hydrochloride H
Structure Name N2-(4-(2-(pynolidin-1-40 NH yl)ethoxy)pheny1)-5-methyl-N4-N (naphthalen-1-yl)pyrimidine-2,4- 20 N diamine Hydrochloride CI is CI NH
N4-(3,4-Dichloro-phenyl)-5-methyl-N244-(2-pyrrolidin-1-yl-N 0,-,No ethoxy)-phenyll-pyrimidine-2,4- 25'7 diamine CIO AI
NH N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(3-15.8 N NH piperazin-l-ylmethyl-pheny1)-NN =pyrimidine-2,4-diamine =
HN el NH
N2-(4-(2-(pyrrolidin-1-ypethoxy)pheny1)-N4-(1H-indol-19.2 N NO 4-y1)-5-methylpyrimidine-2,4-NNSdiamine Hydrochloride = N-(4-(2-(pyrrolidin-1-702.0 yl)ethoxy)pheny1)-4-N
I benzylpyrimidin-2-amine N N
CI
4111 NN2-(4-(2-(pyrrolidin-l-ypethoxy)pheny1)-N4-(4-chloro-3-methoxypheny1)-N4,5- 4900 dimethylprimidine-2,4-diamine N N trifluoroacetate C I oil N4-(4-Chloro-pheny1)-5-methyl-N H N2-[4-(2-pyrrolidin-1-yl-ethoxy)-N phenyll-pyrimidine-2,4-diamine 18'2 N trifluoroacetate Structure Name CI Ai =() WI NH 2- {4- [4-(4-Chloro-3-methoxy-phenyl amino)-5-methyl-9.14 N ()o H pyrimidin-2-y1amino]-phenoxY) N N ethanol 1.1 NH 5-Methyl-N4-phenyl-N2-{4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- 16.7 pyrimidine-2,4-di amine N
N2-(4-(2-(pyrroli din-1 -NH
ypethoxy)pheny1)-5-methyl-N4- 35.7 N p-tolylpyrimidine-2,4-diamine NN Hydrochloride CI
N2-(4-(2-(pyrrolidin-1 -NH ypethoxy)pheny1)-N4-(4-chloro-3-methylpheny1)-5- = 12.4 N methylpyrimidine-2,4-di amine N Hydrochloride CI
N4-(4-Chloro-3-fluoro-pheny1)-F NH 5-methyl-N2-[4-(2-pyrrolidin-1-40.1 N 1(:).N= 0 yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine CI
1.1 N4-(4-Chloro-3-methoxy-0 NH pheny1)-5-methyl-N2-(4-morpholin-4-ylmethyl-pheny1)- 13.3 N
I pyrimidine-2,4-di amine N trifluoro acetate S
NH N4-B enzo [b]thiophen-5-y1-Nethoxy)-phenyl]-pyrimidine-2,4- 28.5 N = I diamine Structure Name N4-B enzo [bithi ophen-3 -y1-5-S
NH methyl-N244-(2-pyrrolidin-l-yl- /9.4 ethoxy)-pheny1l-pyrimidine-2,4-N N\D
I= diamine N
Cl NH N4-(3 -Chloro-pheny1)-5-methyl-N2-[4-(2-pyrrolidin-1 -yl-ethoxy)- 20.8 Ll\I (31\11,D
I=N phenyl] -pyrimidine-2,4-di amine 2-Chloro-N-1244-(2-pyrro1idin-N NH 1-yl-ethoxy)-phenyl amino] -pyrimidin-5-y1 -5-(3- 304 N = C'NtsD
tri fluoromethyl-b enzoylamino)-N N benzamide O N4-(4-Fluoro-3 -methoxy-NH = phenyl)-5-methyl-N2-[4-(2-N 14.8 4111 (:)' pyrrolidin-l-yl-ethoxy)-phenyl]-pyrimidine-2,4-di amine '1\1 0-7\
N4-B enzo [1,3] dioxo1-4-y1-5-NH methyl-N244-(2-pyrrolidin-1-yl-16.9 ethoxy)-phenyl]-pyrimidine-2,4-N diamine N
Cl Ai N4-(4-Chloro-3 -methoxy-NHpheny1)-5-methyl-N2-(3-9.52 piperazin-1-yl-pheny1)-N
pyrimidine-2,4-diamine N N
F31/4, NH N2-(4-(2-(pyrrolidin-1-ypethoxy)pheny1)-N4-(3-N 17.6 N '`NO (trifluoromethyl)pheny1)-5-JL, methylpyrimidine-2,4-di amine '.1\1 ' JAK2 Structure Name 1050 , N2-(4-(2-(pyrroli din-1 -NH yl)ethoxy)pheny1)-N4-(4-(trifluoromethyl)pheny1)-5- 39.8 N"- 0 i methylpyrimidine-2,4-di amine N hydrochloride H
CI isN4-(4-Claloro-3-methoxy-N
43 NH phenyl)-5-methyl-N2-(4-pyrazol- 18.9 O
-N 1-ylmethyl-pheny1)-pyrimidine-NN 2,4-diamine H
r, 0N2-(4-(2-(pyrrolidin-1-Y NH
' yl)ethoxy)pheny1)-5-methyl-N4-(3- 20.7 CF 0..,,,/,..0 (trifluoromethoxy)phenyl)pyrimi N dine-2,4-diarnine Er -CI 0N2-(4-(2-(pyrrolidin-l-F3C NH yl)ethoxy)pheny1)-N4-(4-chloro-23.4 0 C)NO 3 -(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine , N N
H
4110 N4-(3-Methoxy-2-methyl-.
0 NH pheny1)-N244-(2-pyrrolidin-l-yl- 371 C3'-'''"' NO ethoxy)-phenyl]-pyiimidine-2,4-N----,I N di amine H _ a 0 NH
N4-(4-Chloro-3 -methoxy-O NH 0õ0 phenyl)-5-methyl-N2-[4-N 4111 \S' (piperidine-4-sulfony1)-phenyll-N N
pyrimidine-2,4-diamine -,,,,,,.
H
CI 0-cto reoth- 3yl_ ...Ne2t h._ [0474_ ..
-' 5 0 NH r'l\la pNh e417). (y41)-.5 410 NI') i } methyl-pip erazin-1-y1)-phenyll-pyrimidine-2,4-diamine 'N. re" N
H J
Structure Name 1050 .
_ ci 0N4-(4-Chloro-3-methoxy-0 NH 0 phenyl)-5-methyl-N2-(4-N I 4110 N morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine N N
H
CI 0N4-(4-Chloro-3-rnethoxy-0 NH In phenyl)-5-methyl-N2-(4-pyrazol- 35.3 N 0 1-yl-pheny1)-pyrimidine-2,4-I
l\ N
), diamine trifluoroacetate 'r H
CI 0N4-(4-Chloro-3-methoxy-0 NH phenyl)-5-methyl-N2-(4-35.3 1 y piperidin-1-yl-pheny1)-N-N pyrimidine-2,4-diamine H
CI 40N4-(4-Chloro-3-methoxy-.0 NH phenyl)-5-methyl-N244-(4-`)IN el I N--.- methyl-piperazin-l-ylmethyl)-'N'N LN'. phenyfl-pyrimidine-2,4-diamine H
HN \
N4-(1H-indo1-4-y1)-5-methy1-411 NH r.I\I N2-(4-(4-methylpiperazin-1- 9.53 N'-'-j yl)phenyl)pyrimidine-2,4-'Li N =
I diamine Hydrochloride N N
H
CI 0N4-(4-Chloro-3-methoxy-0 NH 'NH phenyl)-5-methyl-N2-(4-6.15 N piperazin-1-yl-pheny1)-NN pyrimidine-2,4-diamine H
CI Oil N4-(4-Chloro-3-methoxy-0 NH pheny1)-5-methyl-(piperidin-4-yloxy)-phenyl]-N N 4.14 pyrimidine-2,4-diamine ,, NH
H
Structure Name H2N 4III NH (--,N- 3- {5-Methy1-2- [4-(4-methy1-0 -,,,-1,.. .4.bi N .N ) piperazin-1-y1)-phenylamino]- 23 1 --y pyrimidin-4-ylamino} -benzamide N IRPIP
H
s l 0 3- {5-Methy1-244-(4-methyl-H2N NH r---N- piperazin-1-y1)-phenylamino]-N 13.6 pyrimidin-4-ylamino} -benzenesulfonamide .-N N
H
CI lis N4-(4-Chloro-3-methyl-pheny1)-NH NH 5-methyl-N2-[4-(piperidin-4- 8.41 N 410 (3'' yloxy)-methyl.
-pyrimidine-2,4-N(,,N
.,-. ,j di amine ..,,,, H
ti? NH N di N-(3- {5-Methy1-244-(piperidin-.141W-H 4-yloxy)-phenylaminci-C)'.' pyrimidin-4-ylatninol-phenyl)-N,N NH aeetami de H _.
' NH .õ,.---,,N,--- N4-B enzo [1,3] dioxo1-4-y1-5-methyl-N2 44-(4-methyl-14.2 CImil N piperazin-l-y1)-phenyll-apyrimidine-2,4-di amine N N
H
CI
N4-(4-Chloro-3-trifluoromethyl-F3C (1P11 NH phenyl)-5-methyl-N2-[4- 11.4 NH 410 0------N-. (piperi din-4-yloxy)-phenyli -N
1 ,2LN
. pyrimi dine-2,4-di amine -,_, 'N , H
HN \
Ci N4-(7-ehloro-1H-indo1-4-y1)-5-SO NH '' methyl-N2 -(444-methylpiperazin-1- 5.36 N) yl)phenyl)pyrimidine-2,4-diarnine N.- N
H _ , Structure Name 0'..NH
le N-(2-Methyl-3-{5-methyl-2-[4-(piperidin-4-yloxy)-NH phenylamino]-pyrimidin-4-N ylaminol-pheny1)-acetamide ,, JL N N NH
H
5-methyl-N4-(2,3-1 dimethylpheny1)-N2-(4-.\%-- NH
(piperidin-4- 4.38 0.,_,Th yloxy)phenyl)pyrimidine-2,4--, r\r N VI NH diamine Hydrochloride H
4111NH 5-methyl-N4-(3,5-dimethylpheny1)-N2-(4-(piperidin-4- 37.2 N =N N ...' 1 .., yloxy)phenyl)pyrimidine-2,4-diamine hydrochloride N' a 0-H
si 1 I.
N N NH r----N 1-(3-{5-Methy1-244-(4-methyl-H H =,:*N . N piperazin-l-y1)-phenylaminoi-63.6 pyrimidin-4-ylaminol-phenyl)-3-N N phenyl-urea H
CI ,,. N4-(4-chloro-3,5-1 , dimethylpheny1)-5-methyl---(4-(4-methylpiperazin-1- 38 =)'=1 N a 1\1.') yl)phenyl)pyrimidine-2,4-diamine Hydrochloride N
H
0 NH N4-(3-tert-butylpheny1)-5-r-N- methyl-N2-(4-(4-1\1') methylpiperazin-1- 4.7 -1NN--. yl)phenyl)pyrimidine-2,4-N
diamine Hydrochloride ________________________________________________________________________ , Structure Name H 0 si . N-Methyl-3-{5-methy1-2-[4-(4--. N,Il NH N-methyl-piperazin-l-y1)-phenylamino]-pyrimidin-4-IN N 16.1 .L ylamino}-benzenesulfonamide -N-H
1 0 el N 1, NH (NV N,N-Dimethy1-3-{5-methy1-2[4-.- -(4-methyl-piperazin-1-y1)-6 N 9.5 tI 001 ylaminol-benzenesulfonamide N N phenylamino]-pyrimidin-4-H
HN \
5-methyl-N4-(7-methy1-1H-S NH ,-----...N...-- indo1-4-y1)-N2-(4-(4-methylpiperazin-1- 3.84 N
N N 40) NN) yl)phenyl)pyrimidine-2,4-tdiamine Hydrochloride ---H
''...,-7.
N4-(3-tert-butylpheny1)-5-I methyl-N2-(4-(piperidin-4-..-i).---NH 2.73 yloxy)phenyl)pyrimidine-2,4-diamine Hydrochloride 'N.,,,-N N NH
H
.
40 N4-(3,5-dimethoxypheny1)-5-NH methyl-N2-(4-(piperidiri-4-yloxy)phenyl)pyrimidine-2,4-i diamine trifluoro acetate ==N,,.-NH
H
0 a F3c N1 N N. NH ,----N. 1-(3-{5-Methy1-244-(4-methyl-H H
ah 1\1) piperazin-1-y1)-phenylaminol-pyrimidin-4-ylammol-pheny1)-3--"N N 11-11F (3-trifluoromethyl-pheny1)-urea H
Structure Name 0 0.,õ
411N 2-Methy1-3- {5-methyl-2-{4-(4-methyl-piperazin-l-y1)-NH 27.8 phenylaminol-pyrimidin-4-N ylaminol-benzoic acid ethyl ester N
N 2-Methyl.-3 {5-methyl-2-{4-(4-NH
phenylamino]-pyrimidin-4-N 1\1) ylaminol-benzamide HN
N4-(1H-indo1-4-y1)-5-methyl-NH N2-(4-(piperidin-4-4.27 yloxy)phenyl)pyrimidine-2,4-I diamine trifluoroacetic acid salt 1\1 N
N2-(4-(2-(pyrrolidin-1-40 yl)ethoxy)pheny1)-N4-(3-tert-NH butylpheny1)-5- 6.71 methylpyrimidine-2,4-diamine N-)'N 0-,-No =Hydrochloride N
N2-(4-(2-(pyrrolidin-l-Sypethoxy)pheny1)-N4-(4-(3-tert-NH butylphenylamino)-5-N="¨\ methylpyrimidin-2-y1)-5-methylpyrimidine-2,4-diamine Nr NN N Hydrochloride 5-Methyl-N4-(2-methyl-3-NH trifluoromethyl-pheny1)-N244-52.9 (piperidin-4-yloxy)-phenyli-PYrimidine-2,4-diamine N
Structure Name H2N.C)" SI 3- {5-Methy1-244-(2-pyrrolidin-NH 1-yl-ethoxy)-phenylaminol-72.2 0 -..,-LN 0 0.õ.õ---.. 0 pyrimidin-4-ylamino } -j..N. N benzenesulfonamide H
Y HN,g el N-Isopropyl-3- {5-methy1-244-ii NH r-N- , (4-methyl-piperazin-1-y1)-0 ,,I.,, N.,,.) 11.8 phenylamino] -pyrimidin-4-1 N is, ylamino} -benzenesulfonamide N N
H
0 lel HN4 N-tert-Butyl-3- {5-methy1-244-..,--..N.---ii NH (4-methyl-piperazin-1-y1)-6.06 0 Nõ,1 1 phenylamino]-pyrimidin-4-ylamino} -benzenesulfonamide N-- N
H
\ / 5-Methyl-N2-[4-(4-methyl-piperazin-l-y1)-phenyll-N443-IP NH õ-----...N.--(pip eridine-l-sulfony)-phenyl] - 24.8 N- pyrimidine-2,4-di amine ..eL N Hydrochloride H .
...--.1-SLN
\ 5-Methyl-N2-[4-(4-methyl-piperazin-1-y1)-phenyl] -N443 -S NH rN- (2-methyl-pip eri dine-1- sulfony)- 33.5 phenyl] -pyrimidine-2,4-diamine Hydrochloride .N ''N
H
NH
N4-(3-Methanesulfony1-4-Ii r---N-methyl-pheny1)-5-methyl-N244-0 N.,._,--1 160 I 11 0 (4-methyl-piperazin-l-y1)-phenyl] -pyrimidine-2,4-diamine `N N
H
Structure Name NI el NH N-Cyclohexy1-3- {5-methyl-2-[4-- T, (4-methyl-pip erazin-l-y1)-0 0 L.N 0 rt\I
N,,,..) phenyl amino] -pyrimidin-4- 39.4 1 ,[,. ylamino } -benzenesulfonamide '-' Nr N
H
-1) 0 (...N. N,N-Diethyl-3- {5-methyl-2-[4-NH
0 , N .,) (4-methyl-piperazin-l-y1)-60.3 1 y 0110 phenylamino] -pyrimidin-4-N N ylamino } -benzenesulfonamide ' H
.F3 4111 N4-(3 -(trifluoromethyl)-2-methylpheny1)-5-methyl-N2-(4-NH rN.- (4-methylpip erazin-1- 87.1 yl)phen yl)pyrimidine-2,4-I
N N
diamine hydrochloride `r H
ON 01 (3- 15-Methy1-244-(pip eridin-4-NH
yloxy)-phenylamino]-pyrimidin-N0 (31'`-- 4-ylamino} -pheny1)-pyrrolidin-1-\1 N NH * yl-methanone -.,.
.1 H
H N-Cyclopenty13- {5-Methyl-2-[4-1110(4-methyl-pip erazin-l-y1)-NH .õ0õ----..N.-, phenyl amino] -pyrimidine-4- 19.8 1\1) yl amino } -benzenesulfonarnide '...)., Hydrochloride N N
H
0 ,c------0z-s/LN
\---- 5-Methyl-N2-[4-(4-methyl-LIP piperazin-l-y1)-phenyl]
NH __.----..N.--(pyrrolidine-l-sulfony)-pheny1]- 17.1 N) pyrimidine-2,4-diamine i Hydrochloride leNNI
H
Structure Name o,-----,,õ
1.N,0,, ifti NH N-piperazin-1-y1)-pheny11-N443-5-Methyl-N244-(4-methyl-II
20.7 0 --....õ,--1,-z,N 0 N..,,s,......--(morp1o1ine-4-su1fony1)-pheny1i -N
1 pyrimidine-2,4-di amine =N
H _ NH r..N. N-Isopropyl-371 5 -methy1-2-{4-(4-methyl-piperazin-1 -y1)-0 N.) 541 N
phenylarnino] -pyrimidin-4-N
..,.. N 0 ylaminol-benzamide H
I
0=S=0 methy1pip erazin-1 el ......----...N. 5-methyl-N2-(4-(4--yl)pheny1)-NH N4-(3- 215 '-)*1 N . NI') (met hylsulfonyl)phenyl)pyrimidi i ne-2,4-diamine 'N N
H
A.N
NH
N-tert-Butyl-3- {5-methy1-244-ry 0 I\12 (4-methyl-pip erazin-1 -y1)-L.'N
0 phenyl amino] -pyrimidin-4-jyl amino 1 -benzami de N N
H
.
0=S=0 5-methyl-N2-(4-(4-SiNH methylpiperazin-1-yl)pheny1)-N4-(3- 8 r N - (propylsulfonyl)phenyl)pyrimidin 0 N`) e-2,4-di amine i ..
'N N
H
5-Methyl-N2-[4-(4-methyl-42.5 N- _y1)-pheny1]-N4-(3-N4 pip erazin-1 HN 42 .5 N'N 0 N) piperidin-4-yl-phenyl)--.,N *N pyrimi dine-2,4-di amine H
Structure Name _ '''....../
HN N-tert-Butyl-345-methy1-2-(4-,11 S NH morpholin-4-ylmethyl-1 I 12.5 0 ii 0 N phenyl amino)-pyrimidin-4-NN 0 ylaminol-benzenesulfonamide H
r, /0 1---=S-/--NH
N-tert-Butyl-345-methy1-2-(4-piperazin-l-yl-phenyl amino)-NH rNH pyrimidin-4-ylaminol- 7.59 -)..1 N . N') benzenesulfonamide ' Hydrochloride N N
H
uN
Y N443 -(2,5-Dimethyl-pyrrolidine-1-sulfony1)-phenyl] -5-methyl-NH r-N- N244-(4-methyl-piperazin-l-y1)- 18.8 e phenyllpyrimidine-2,4-di amin N 0 N') Hydrochloride 1 1,.
N N
H
G'H
\<- N-tert-Butyl-3 -(2- {44442-S NH OH hydroxy-ethyl)-piperazin-l-yl] --,N phenyl amino } 45-methyl-7.09 N.,,) pyrimidin-4-ylamino]-"N
I ),, benzenesulfonamide ' NN 0 Hydrochloride H
`,.----HN el NH N-tert-Butyl-345-[5-2-(4-,cil ii r----- pyrazol-1 -yl-phenylamino)-,,,I., / pyrimidin-4-ylaminoi -0 40 N, 1 '`I\I N
.N.A'N benzenesulfonamide H
\./
HN N-tert-Butyl-345-[5-2-(6-, III
IT NH (NH
pip erazin-l-yl-pyridin-3 -0 NN) yl amino)-pyrimidin-4-ylamino]--,N-- N.------..-z.. b enzenesulfonami de H
Structure Name 2-[4-(3- {5-Methy1-244-(4-NH N methyl-pip erazin-l-y1)-HO phenyl amino] -pyrimidin-4- 8.46 yl amino } -pheny1)-piperidin-1-N N A-ethanol N-tert-Buty1-345-methy1-2-(3-101morpholin-4-ylmethyl-7.06 NH phenyl amino)-pyrimidin-4-yl amino] -b enzenesulfonamide r0 N N
N-tert-Butyl-345-[5-2-(4-HN ,913c* NH pyrazo1-1-ylmethyl-18.6 0 N N phenyl amino)-pyrimidin-4-I [N, yl amino } -b enzenesulfonami de N N
O el HN,g NH N-tert-Butyl-3- {5-methyl-243 -(piperidine-1-sulfony1)-phenyl amino]-pyrimidin-4-N N ylamino } -benzenesulfonamide 0 IP N-tert-buty1-3- f[5-methy1-24 {4-NH
HN [(4-methylpiperazin-1-'S
I
0 yl)methyl]phenyl} amino)pyrimid 29.8 N in-4-N yl] amino } b enzenesulfonamide O NH CF3 N-tert-butyl-3-[(5-methyl-2- {[4-NH
HN
4111 pip erazin-l-y1-3 O N (trifluoromethyl)phenyl] amino } p 22.5 Si yrimidin-4-N yl)amino]benzenesulfonamide &TALC
Structure Name 0 3-[(2- { [4-(4-acetylpiperazin-1-HN , g ? NH CF3 ( N --1C
6 - ).. N ,1 (trifluoromethyl)phenyl] amino } - 35.7 1 11 * 5-methylpyrimi din-4-y1) amino] -... IN( N N-tert-butylb enzenesul fonami de H
r, õ0 'S-NH
`
110 NHN-tert-Buty1-345-methy1-2-(3 -piperazin-1-yl-phenylamino)-pyrimidin-4-ylamino] - 18 \/Li .1. ei benzenesulfonamide Hydrochloride - N-....N1 H
c.,-NH
r, 0'9 NH
=<" N-tert-Butyl-3-(2- {34442-hydroxy-ethyl)-pip erazin-l-yl] -la NH phenylamino } 45-methyl-40.5 pyrimidin-4-ylamino] -i benzenesulfonamide N N N..-.1 Hydrochloride H
IN-'0H
',-../.
141111 N-tert-butyl-3- {[5-methyl-2-( {3 -HN,QH
if NH [(4-methylpip erazin-1 -0 -.,..-L, 'N N. yl) sulfonyl]phenyl ] amino)pyrimi 650 1 ),, el 9 0 din-4-Nr. N S".1\1 yl] amino } b enzenesulfonami de 0N-tert-butyl-3 -[(5-methy1-2- { [4-HN,g 1411) (piperazin-1-L
ylmethyl)phenyl] aminolpyrimidi 4.6 I
n-4--.....õ--0 N N.) L.,----__. NH
yl)amino]benzenesulfonamide = N-- I. N
H
9\ 140 NH N
5-Methyl-N2.-[4-(4-methyl-0 NIr--) pip erazin-l-y1)-phenyl] -N443 -rS 'NN--N el N
HN, eridine-4-sulfon 1 -heny1]-(PiP Y ) 13 pyrimidine-2,4-diamine '1\1 N
H
Structure Name .
5-methyl-N2-(4-(4-,--..Nõ--N el NH methylpiperazin-1-yl)pheny1)-* NN.---- N4-(3-(piperidin-1- 46.3 i 4 yl)phenyl)pyrimidine-2,4-'N.N.N diamine H _ N4-(3-(1H-pyrrol-1-yl)pheny1)-5-al SI NH (N methyl-N2-(4-(4-0 N') methylpiperazin-1- 33.8 -(NN yl)phenyl)pyrimidine-2,4-diamine H
H
NH
rN 3- (5-Methy1-244-(4-methyl-piperazin-l-y1)-phenylaminol-HN., 0 N,,,2 'N-.= --,-'''Ll el pyrimidin-4-ylaminoI-N- 543 piperidin-4-yl-N
H benzenesulfonamide HN-N
\
S NH N4-(1H-indazol-4-y1)-5-methyl-N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-I 1,, diamine Hydrochloride L
H
HN \
Si NH N4-(1H-Indo1-4-y1)-5-methyl-N2-(4-morpholin-4-ylmethyl- 7.42 N alb N'= pheny1)-pyrimidine-2,4-diamine `N*N VI 10 H
HN \
el NH N4-(1H-Indo1-4-y1)-5-methyl-N2-(4-piperazin-l-ylmethyl- 10.1 N 5 N) pheny1)-pyrimidine-2,4-diamine .. A, LNH
N N
H
Structure Name H
>-N-,:s\ NH N-tert-Butyl-3- {5-methyl-2-[4-0 \0 (2-pyrroli din-1 -yl-etho xy)-12.5 401 N.ILD phenyl aminol-pyrimidin-4-N N yl amino } -benzenesulfonamide HO NH
3 -(2-(4-(piperidin-4-yloxy)phenylamino)-5-- C) 51.9 methylpyrimidin-4-ylamino)phenol / NH
CI
N2-(4-(2-(pyrrolidin-l-yl)ethoxy)pheny1)-N4-(7-chloro-HN 1H-indo1-4-y1)-5- 1.16 NN Si NO methylpyrimidine-2,4-di amine Hydrochloride /NH
N2-(4-(2-(pyrrolidin-l-yl)ethoxy)pheny1)-5-methyl-N4-HN (7-methyl-I H-indo1-4- 6.98 -1 yl)pyrimidine-2,4-diamine NN SiHydrochloride / NH
F
N2-(4-(2-(pyn-olidin-l-yl)ethoxy)pheny1)-N4-(7-fluoro-HN 1H-indo1-4-y1)-5- 9.28 NO methylpyrimidine-2,4-di amine N Hydrochloride CI Am o Wi NHN4-(4-Chloro-3-methoxy-NH pheny1)-5-methyl-N2-(6-12.1 N piperazin-1 -yl-pyridin-3 -y1)-NN pyrimidine-2,4-di amine Structure Name SI 544-(4-Chloro-3-methoxy-0 NH 0 0 ("...N phenylamino)-5-methyl-H pyrimidin-2-ylamino]-2- 5.12 N N
piperazin-l-yl-benzoic acid N methyl ester LIP
0 0 544-[4-4-NH ylamino)-5-methyl-pyrimidin-2-ylamino]-2-(2-pyrrolidin-l-yl- 16.4 N '-'NtD
ethoxy)-benzoic acid methyl ester >1\1,,s, NH N-tert-Butyl-3-{5-methyl-244-[4 (piperidin-4-yloxy)-0"0 7.3 Nphenylaminol-pyrimidin-4-I
el NH ylamino}-benzenesulfonamide HN
N4-(1H-Indo1-5-y1)-5-methyl-NH
N2-[4-(piperidin-4-yloxy)-N (:)N1 phenyfl-pyrimidine-2,4-diamine N NH
. H.
ah 0 2- {544-(Benzo[1,3idioxo1-4-NH ylamino)-5-methyl-pyrimidin-2-N
1 ethanol 0¨\
N4-Benzo[1,3]dioxo1-4-yl-N243-NH methoxy-4-(2-pyrrolidin-l-yl-9.34 ethoxy)-pheny1]-5-methyl-N C)NID
=pyrimidine-2,4-diamine '1\1 N
Structure Name H
..õ-N, 410 NH N N-tert-Butyl-3 -[2-(4-imi dazol-1-/A\ [---:----- yl-phenyl amino)-5-methyl-0 0 N 0 1\L' pyrimiclin-4-ylaminoi- 12.3 I benzenesulfonamide .si\( N
H
H
>NH N,,,,s\ el N-tert-Butyl-3 42-(4-imidazol-1 -o' \o ylmethyl-phenylamino)-5-8.42 N N
Y:11 . NZN methyl-pyrimidin-4-ylamino]-benzenesulfonamide H
H
r ..N,./S\ NH ISI N-tert-Butyl-3-{2-[4-(2-hydroxy-ethoxy)-phenyl amino] -5-methyl-,L, 1 1\1 0 CIOH pyrimidin-4-ylamino } - 20.3 c o -:NL N benzenesulfonamide H
\,-0:.-zg-NH
N-tert-Butyl-3- {5-methy1-244-101 NH (4-oxy-morpholin-4-ylmethyl)-48.6 phenyl amino] -pyrimidin-4-0- yl amino 1 -benzenesulfonamide 'LN
N N VI Aki II\1+Th Lo CI it&
N4-(4-Chloro-3-methoxy-o 4-F NH phenyl)-5-methyl-N2-(4-15.2 I N--'. piperazin-1-ylmethyl-phenyl)-I\IN qW1 NH pyrimidine-2,4-di amine ' -,,,, H
H
>N,,,s\ lelNH \)---_,..:N N-tert-Butyl-3-{5-methy1-244-(2-methyl-imidazol-1-y1)-cro 1 1 0 N,/} 34.3 phenyl amino]-pyrimidin-4-yl aminol-b enzenesulfonamide 'µN N
H
H
>N;s\ II N-tert-Butyl-3- IS-methyl-244-[4 NH (2-methyl-imidazol-1-ylmethyl)-21.9 c)/ \(:) '-----'L-H.I 0 Nt...,__I-4N phenylaminol-pyrimidin-4-ylamino}-benzenesulfonamide ..1\1 N
H
, Structure Name H
>N..,/s\ Si NH N-tert-Butyl-3[5-methy1-2-(4-pyridin-4-ylmethyl-0"0 80.7 N
IN 4111 phenylamino)-pyrimidin-4-1\ . N ylaminol-benzenesulfonamide .'r H
H
>- S\
0 NH N-tert-Butyl-345-[5-2-(4-cro = N morpholin-4-yl-phenylarnino)-benzenesulfonamide ,N) 12.1 pyrimidin-4-ylaminoi-'IeN
H
ialli NH'D -(4-(1H-pyrazol-1-yl)pheny1)-1\1 ,I/ N2 N4-(3-tert-butylpheny1)-5- 151 I ), methylpyrimidine-2,4-diamine 'i\r N
H
HN \
CI gib RP N4-(7-chloro-1H-indo1-4-y1)-5-NH
methyl-N2-(4-((piperazin-1-N
N
yl)methyl)phenyl)pyrimidine-2,4-I diamine Hydrochloride -'i\r N 411 NH
H
110 NH 1\1\ N4-(3-tert-butylpheny1)-5-methyl-N2-(4-(2-methy1-1H-38.4 110 Nj imidazol-1-yl)phenyl)pyrimidine-,, N N 2,4-diamine Hydrochloride -`
H
N4-(3-tert-butylpheny1)-5-rN, methyl-N2-(4-(2-methy1-1H-Nd¨ 94.1 N
= 110 1\1*N imidazol-1-yl)phenyl)pyrimidine-2,4-diamine Hydrochloride H
H
N-tert-Buty1-345-methy1-2-(4-NH
[1,2,4]triazol-1-ylmethyl-0"0 ,),, 35.4 jkl., 0 N.N phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide N N L---:-N
H
Structure Name H
NHI,----_\._ N-t ert-Buty1-3 - { 5-methyI-2- [4-(4-methy1-imidazol-1-y1)-, 0 N 40 N'" phenylamino]-pyrimidin-4- 41.7 i N, N yl amino } -benzenesulfonamide .' H
2,N-Dimethy1-5- f5-methy1-244-[4 .--- N-Is\ NH (2-pyrrolidin-1-y1-ethoxy)-6\0 .-)''1\1 Si -N) phenyl amino} -pyrimidin-4-N*N ylamino } -benzenesulfonamide H
H
s ...N.;, 0 NH N-tert-Buty1-2-methy1-5- {5-1 0/. 4/0 0No methy1-2-[4-(2-pyrrolidin-1-y1-44.4 j,. ethoxy)-phenyl amino] -pyrimi din-\' N N 4-ylamino } -benzenesulfonamide H
H
N,,s \ 1.0 NH iii N-tert-Butyl-345-methyl-2-(4-----N [1,2,4}triazol-1-yl-phenylamino)-6 b ,N)õ Si N,,./,,,,' p yrimidin-4- ylaminol- 41.4 tNN benzenesulfonamide H
-') NH 4111 .Sµ NH N-tert-Buty1-3- {5-methy1-243-(1H-tetrazol-5-y1)-phenylamino]- 55.9 pyrimidin-4-ylamino I-t NN 0 )\1 benzenesulfonatnide H,,N
HN-N
H (11101 N, __N N-tert-Buty1-542-(4-imidazol-1-A\ NH
0 0 N)yl-phenylamino)-5-methyl-88.2 N
N
pyrimidin-4-ylarnino] -2-methyl-b enzenesulfonamide N
H
H
NH N-tert-Butyl-3- {5-methy1-244-(pyrrolidine-1 -earbony1)-0 0 33.5 - 0 0 phenylaminoi -pyrimidin-4-jj, ylamino} -benz enesulfonamide N N
hl CA 02628283 2008-05-01 .
_ JA.K2 Structure Name . 1050 , H
>, N , NH N-tert-Buty1-3- {5-methy1-244-0 0 0 (morpho line-4-carb ony1)-32.9 '-''-)N 0 N phenyl aminoFpyrimidin-4--, N 1-..,..0 y1amino)-benzenesulfonamide " N
H
H
>' S\
40 NH 0 N-tert-Butyl-3- {5-inethy1-244-(pip erazine-1 - carb ony1)-0 "
N ---') phenyl aminoj-pyrimi din-4-L
L. NH Amino} -benzenesulfonamide N
H
NH HN N-tert-Buty1-3- {5-methy1-2-{4--Nõ
,N (1H-tetrazol-5-y1)-phenylaminol-96.7 N
N
N pyrimidin-4-ylamino} -benzenesulfonamide Thq 14111 H
1101 N4-(3-tert-butylpheny1)-5-NH
methyl-N2-(4-(1-moTholinoethyl)- 19.9 phenyl)pyrimidine-2,4-diamine N O0 Hydrochloride li H
>'N `1S, o\ 41111 NH (N'N -..-= 3- {244-(4-Acetyl-piperazin- 1-y1)-phenyl amino1-5-methyl-0 -,,iõ N .,) 18.6 t"11, Spyrimidin-4--ylamino} -N-tert-N.-- N butyl-benzenesulfonamide H
1.1 NH NH N4-(3-tert-butylph eny1)-5-rnethy1-N2-(4-(piperidin-4-20.9 Si , yl)phenyl)pyrimi dine-2,4-diamine Hydrochloride N N
H
>,..N,sis\ * NH N-tert-Butyl-3- {5-methy1-244-(1 -morpholin-4-yl-ethyl)-01-\ 0 , 29.7 i N N phenyl amino] -pyrimidin-4-NN14111 1,,o ylamino } -b enzen esulfon amide H
Structure Name 5-methyl-N4-(2,3-, I dimethylpheny1)-N2-(4-(4-methylpiperazin-l- 16 N
NN yl)phenyl)pyrimidine-2,4-diamine Hydrochloride CI
N4-(4-chloro-2-methylpheny1)-5-NH methyl-N2-(4-(4-N methylpiperazin-1- 15.9 yl)phenyl)pyrimidine-2,4-diamine Hydrochloride 5-methyl-N4-(3,4-N H I dimethylpheny1)-N2-(4-(4-methylpiperazin-1- 16.6 = yl)phenyl)pyrimidine-2,4-N N diamine Hydrochloride EXAMPLE 245. Determination Of Efficacy Of Selected Ccompounds [0468] HEL, CTLL-2 & nonnal human dermal fibroblasts (NHDF) were from the American Tissue Culture Collection Rockville, MD). BaF/3 cells were obtained from DKFZ
Cancer Research Center (Heidelberg, Germany).
[0469] BaF/3, HEL & NHDF cells were grown in RPMI 1640 medium (Gibco BRL, Gaithersburg, MD) supplemented with penicillin, streptomycin, L-glutamine, and 10% fetal bovine serum (FBS). CTLL-2 cells were grown in the same media further supplemented with 20 U/mL recombinant IL-2 (Hoffmann-LaRoche, Nutley, NJ). Plasmid containing the human JAK2 coding sequence was purchased from Invitrogen (Madison, WI). JAK2v617F
cDNA
was generated by using site-directed mutagenesis to introduce the V617F
mutation into the human JAK2 coding sequence followed by verification using two-directional sequencing.
This cDNA was subsequently subcloned into a retroviral vector and transduced into BaF/3 cells. Permanently transduced BaF/3 cells expressing JAK2v617F were selected and maintained with 1 mg/m1 G418. GFP was introduced into this cells by lentiviral transduction using pLenti6-GFP (Invitrogen) followed by selection with blasticidin and confirmation of GFP expression using FACs analysis.
[0470] Cell proliferation assay was performed using the XTT cell proliferation kit according to the manufacturer's instructions (Roche, Alameda, CA). In brief, approximately 2.5 X 103 cells were plated in triplicate into microtiter-plate wells in 100 uL RPMI growth media plus various doses of XLV. After 72 hour incubation twenty microliters of XTT was added to the wells and allowed to incubate for 4-6 hours. The colored fonnazan product that is formed was measured spectrophotometrically using the Vmax spectrophotometer (Molecular Devices, Sunnyvale, CA) at 450 nm with correction at 650 rim. IC50 values were determined using the GraphPad Prism 4.0 software (San Diego, CA), wherefore OD
values were plotted on y-axis (linear scale) and concentration (mM) on the x-axis (log scale). Data was subjected to a non-linear regression fit analysis and IC50 values were detennined as the concentration which inhibited proliferation 50%.
[0471] Proliferation EC50:
HEL ¨ 270 nM
Baf3:JAK2V617F ¨297 nM
Control data: IL-2-induced JAK3-dependent proliferation ¨ 3395 nM
Control data: Normal human dermal fibroblast control ¨ 6487 nM
Apoptosis assays [0472] BaF/3-JAKv617F cells cultured in growth medium (RPMI, 10%FBS, 1 mg/ml and 10 p.g/mlblasticidin) were treated with XLV at 1, 3 and 10 uM for 24 h.
Following harvesting cells by centrifugation at 890 RCF (relative centrifugation force) for 5 mm, genomic DNA was isolated from cell pellets using a DNA isolation kit (Puregen, Chino, CA).
jig genomic DNA of each sample was subjected to 1.2% agarose gel electrophoresis to detect genomic DNA fragmentation (DNA laddering assay). As a control, adherent noinial human dennal fibroblasts (NHDF) cultured in growth medium (Cambrex, Walkersville, MD) at 60% confluence were treated with XLV as described above. Following 2 washes with ice cold PBS, genomic DNA was isolated from the NHDF cells for agarose gel electrophoresis.
Immunoblotting [0473] BaF/3-JAKv617F cells treated with XLV or vehicle control were centrifuged, washed 2X with ice-cold PBS and lysed using RIPA buffer. Protein concentration was determined using the BCA method (Pierce, Rockford, IL) and 100 jig of total cellular protein of each sample in 1X Laemmli buffer were subjected to Western blot analysis.
The protein blot was probed with an anti-phospho-STAT5 (Tyr694/699) (Upstate Biotechnology, Charlottesville, VA), subsequently stripped and re-probed with an anti-STAT5 antibody (Cell Signaling Technology, Danvers, MA). The phospho-STAT5 or STAT5 protein was visualized by the enhanced chemoluminescence method (Pierce). In vivo signaling studies were done in a similar fashion. Briefly, on day 11 after cell injection, animals were orally dosed with either vehicle or 100 mg/kg of XLV. Spleens were harvested 7 h after dosing and quickly homogenized in a FastPrep machine (Qbiogen, Irvine, CA). 100 pg of each spleen homogenate were subjected to Western blot analysis. The protein blot was probed with an anti-phospho-STAT5 (Tyr694/699) and subsequently with an anti-STAT5 antibody and visualized by the enhanced chemolumine,scence method.
FACs analysis of circulating tumor burden [04741 On day 11 after injection of BaF/3-JAK2v617F cell suspension, 1 mL
blood was collected by a terminal cardiac bleeding method from one mouse that received vehicle, moreover, 0.1 mL blood was collected by a non-lethal retro-orbital collection method from mice of each of the three groups dosed with 10, 30 or 100 mg/kg of XLV and pooled together within the dose groups. Blood mono-nucleated cells were isolated by a Ficoll (Sigma-Aldrich, St. Louis, MO) cushion centrifugation method (600 RCF and 30 min). The isolated cells were subjected to FACS analysis to determine the percentage of OFF positive BaF/3:JAK2v617F cells. The results are shown in Figure 1.
Circulating Tumor Model [0475] SCID mice were intravenously injected with BaF/3 cells expressing JAK2v617F and GFP. XLV was dosed orally at the indicated doses beginning 3 days after infusion and ending 20 days after infusion. On day 11 blood was taken from animals in each group and subjected to FACs analysis to determine the percentage of circulating cells which were GFP
positive. In a parallel study animals were treated as described above with the exception that they were given a single 100 mg/kg dose of drug on day 11 followed 4 hours later by sacrifice and analysis of STAT5 phosphorylation in the tumor-bearing enlarged spleen. The results are shown in Figure 2.
Ocular exposure and efficacy data 10476] Exposure data of compounds at 0.1% via eye drop administration:
[0477] On topical dosing of compounds fonnulated as 0.1% doses in 0.2%
tyloxapo1/1%
HPMC/4% Mannitol, exposure levels in found in back of the eye tissues of the mouse are shown at two different time points, namely at 2 h and at 7 h. The efficacy data for selected compounds are shown in Table 2.
Concentration (nM) in mouse ocular tissues following bilateral topical instillation of 0.1% formulation QDX1 Concentration (nM) Formulation concentration for selected compounds Time (hr) retina Sclera/choroid Cornea 0.1% XVII 2 495 6040 8840 0.1% X.XXVI 2 816 7250 7870 0.1% XLIV 2 406 4840 103000 0.1% LXXXII 2 267 2340 69900 0.1% LXXIV 2 2120 6090 45000 EXAMPLE 246. Compound XVII in an Ocular efficacy study in an oxygen-induced retinopathy (OIR) model [0478] Compound XVII was tested using the mouse oxygen-induced retinopathy (OIR) model, in which retinal neovascularization is triggered by cycling mouse pups from normoxia to hyperoxia and then back to normoxia. Litters of C57BL/6 mice were transferred to a hyperoxic environment (70% 02) starting on postnatal day 7 (P7). After 5 days, litters were returned to a nounoxic environment (21% 02), where they were then maintained for an additional 5 days, during which time they received topical applications of either compound XVII or an appropriate vehicle. At the end of this period, retinal whole-mounts were prepared and stained with a fluorescently-labeled lectin (BSL I) that recognizes murine endothelium. Finally, digital images were obtained by fluorescence microscopy and analyzed with an image analysis software program in order to quantify vascular area. In one study, animals dosed with a 0.1% formulation of compound XVII twice daily (bid) showed a 29%
reduction in vascular area as compared to vehicle-treated animals (P<0.05, a=
11-15); in a second study, a 22% reduction was observed (P<0.02, n 6). The results are summarized in Table 3.
Vascular Area % Change vs.
Study # Treatment Group (nun2, mean SD Vehicle Control Vehicle 4.9 1.6 0.1% XVII 3.5 th 0.6 -29%
Vehicle _________________________ 8.3 th 0.8 0.1% XVII 6.4 1.6 -22%
104791 Although the invention has been described with reference to the above examples, the scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.
-%1\1 IC)L1 =-N)N.N
CXL VII
[0431] A mixture of intermediate 77 (0.15 g, 0.5 mmol) and 4-(4-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.65 mmol) were diluted with HOAc (5 mL) and microwaved at 150 C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.091 g, 41%).
[0432] NMR (500 MHz, DMSO-d6): 8 1.71-1.78 (m, 2H), 2.02-2.08 (m, 8H), 2.16 (s, 3H), 3.09 (br s, 2H), 3.24 (br s, 2H), 4.50-4.52 (m, 1H), 6.77 (d, J= 8.4 Hz, 2H), 7.09-7.15 (m, 3H), 7.27 (t, J= 7.9 Hz, 1H), 7.49 (d, J= 8.1 Hz, 1H), 7.86 (s, 1H), 8.54 (br s, 1H), 8.59 (br s, 1H), 9.45 (s, 1H), 9.84 (br s, 1H), 10.34 (br s, 1H). MS (ES+): in/z 447 (M+H)+.
EXAMPLE 223. 5-Methyl-N2-[4-(4-methyl-piperazin-l-y1)-phenyl]-N4-(3-nitro-phenyl)-pyrimidine-2,4-diamine (Intermediate 78) =
v211 NH N-N') N
[0433] A mixture of 1-bromo-3-nitro-benzene (0.77 g, 3.8 mmol), intermediate 32 (0.95 g, 3.2 mmol), Pd2(dba)3 (0.29 g, 0.32 mmol), Xantphos (0.37 g, 0.64 mmol) and cesium carbonate (3.1 g, 9.6 mmol) were suspended in dioxane (40 mL) refluxed for 16 h. The reaction mixture was then cooled to room temperature, filtered and solvents evaporated.
Resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.53 g, 40%).
EXAMPLE 224. 1V4-(3-Amino-phenyl)-5-methyl-N2- 4-(4-methyl-piperazin-1-14)-phenyl]-pyrimidine-2,4-diamine (Intermediate 79) L-1\1 410 N) N N
[0434] Slurry of intermediate 78 (0.23 g, 0.54 mmol) in Me0H (25 mL) was purged with argon and treated with Pd/C 10% wt. (0.18 g). Reaction atmosphere was replaced with hydrogen and stirred for 4 h. Hydrogen balloon was then removed and argon was flushed through reaction before filtration through Celite. Solvents were then evaporated to pale brown solids (0.17 g, 83%).
EXAMPLE 225. 1-(345-Methy1-2-14-(4-methyl-piperazin-l-y1)-phenylaminol-pyrimidin-4-ylaminol-pheny1)-3-phenyl-urea (Compound CXLVIII) ei ei N N NH r'NN
H H
40, N'`) N N
CXLVIII
[0435] A suspension of intermediate 79 (0.17 g, 0.45 mmol) in DCM (10 mL) was treated with phenyl isocyanate (0.058 mL, 0.54 mmol) and stirred for 1 hour. Reaction solvents then removed and resulting residue purified by HPLC to provide title compound as white solids (0.075 g, 33%).
[0436] 114 NMR (500 MHz, DMSO-d6): 6 2.09 (s, 3H), 2.15 (s, 3H), 2.30-2.32 (m, 4H), 2.92-2.94 (m, 4H), 6.74 (d, J¨ 8.4 Hz, 2H), 6.94-6.97 (m, 1H), 7.19-7.28 (m, 5H), 7.45 (d, J
8.8 Hz, 2H), 7.53 (d, J= 9.0 Hz, 2H), 7.73 (br s, 1H), 7.83 (s, 1H), 8.23 (s, 1H), 8.68 (s, 1H), 8.74 (s, 1H), 8.78 (s, 1H). MS (ES+): in/z 509 (M+H)+.
EXAMPLE 226. 143-15-Methy1-2-f444-methyl-piperazin-1-171)-phenylaminol-pyrimidin-4-ylaminol-phenyl)-343-trifluoromethyl-pheny1)-urea (Compound CXLIX) F3 eiN N NH
H H
N INL') N N
CXLIX
[0437] A suspension of intermediate 79 (0.1 g, 0.26 mmol) in DCM (8 mL) was treated with 1-isocyanato-3-trifluorornethyl-benzene (0.043 mL, 0.31 mmol) and stirred for 1 hour.
Reaction solvents then removed and resulting residue purified by HPLC to provide title compound as white solids (0.039 g, 26%).
[0438] 114 NMR (500 MHz, DMSO-d6): 8 2.16 (s, 3H), 2.82 (s, 3H), 2.86 (br s, 2H), 3.08 (br s, 2H), 3.42 (br s, 2H), 3.69 (br s, 2H), 6.88 (d, J= 8.4 Hz, 2H), 7.20 (br s, 1H), 7.29-7.33 (m, 5H), 7.52 (t, J= 7.9 Hz, 1H), 7.57 (d, J= 8.5 Hz, 1H), 7.77 (s, 1H), 7.84 (s, 1H), 8.09 (s, 1H), 9.42 (s, 1H), 9.66 (s, 1H), 9.71 (br s, 1H), 10.1 (br s, 1H). MS (ES+):
777/Z 577 (M+H)+.-EXAMPLE 227. (2-Chloro-5-methyl-pyrimidin-4-y1)-(2-methvi-3-trifluoromethyl-pheny1)-amine (Intermediate 80) =
POI
N CI
[0439] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.18 g, 5.9 mmol), 1-bromo-2-methyl-3-trifluoromethyl-benzene (0.33 g, 1.4 mmol), Pd2(dba)3 (0.12 g, 0.13 mmol), Xantphos (0.15 g, 0.25 mmol) and cesium carbonate (1.23 g, 3.8 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 18 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.095 g, 25%).
EXAMPLE 228. 5-Metirvi-N4-(2-methyl-3-trifluoromethyl-pheny1)-N244-(piperidin-yloxy)-phenyll-pyrirnidine-2,4-diamine (Compound CL) F3c NH
N N NH
CL
[0440] A mixture of intermediate 80 (0.058 g, 0.2 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.073 g, 0.25 mmol) were diluted with HOAc (5 mL) and microwaved at 150 C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.025 g, 30%).
[0441] 1H NMR (500 MHz, DMSO-d6): 8 1.71-1.78 (in, 2H), 2.00-2.04 (m, 2H), 2.18 (s, 3H), 2.25 (s, 3H), 3.08 (br s, 2H), 3.22 (br s, 2H), 4.50-4.52 (m, 1H), 6.70 (d, J= 8.3 Hz, 2H), 7.10 (d, J= 8.9 Hz, 2H), 7.54 (t, J= 7.8, 1H), 7.62 (d, J= 7.7 Hz, 1H), 7.75 (d, J= 7.8 Hz, 1H), 7.91 (s, 1H), 8.54 (br s, 1H), 8.61 (br s, 11-1), 9.88 (s, 1H), 10.34 (br s, 1H). MS
(ES+): ni/z 458 (M+H)+.
EXAMPLE 229. (3-13romo-phenyl)-pyrrolidin-1-yl-rnethanone (Intermediate 81) ON Si Br [0442] A solution of 3-bromo-benzoyl chloride (2.7 g, 12 mmol) in DCM (40 mL) was chilled to zero degrees and treated with pyrrolidine (3 mL, 36.8 mmol).
Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (3.1g, 100%).
EXAMPLE 230. [3-(2-Chloro-5-methyl-pyrimidin-4-ylarnino)-phenyll-pyrrolidin-1-yl-methanone (Intermediate 821 NH
ON
CI
[0443] A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.22 g, 1.5 mmol), intermediate 81 (0.46 g, 1.8 mmol), Pd2(dba)3 (0.14 g, 0.15 mmol), Xantphos (0.17 g, 0.3 mmol) and cesium carbonate (1.5 g, 4.5 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 18 min. Reaction vessel was then centrifuged down and decanted.
Solvents then evaporated and resulting residue was purified by flash chromatography on silica gel to afford title compound as white solids (0.25 g, 53%).
EXAMPLE 231. (3-15-Methy1-2-1-4-(piperidin-4-y1oxy)-pheny1amino1-pyrimidin-4-ylarninol-pheny1)-pyrrolidin-1-yl-methanone (Compound CLI) NH
411, ,N*N
CLI
[0444] A mixture of intermediate 82 (0.1 g, 0.32 mmol) and 4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.12 g, 0.41 mmol) were diluted with HOAc (6 mL) and microwaved at 150 C for 15 min. Solvents then removed and resulting residue purified on HPLC. Title compound isolated as white solids (0.005 g, 3%).
[0445] 1H NMR (500 MHz, DMSO-d6): 8 1.74-1.81 (in, 4H), 1.83-1.88 (in, 2H), 2.05-2.09 (in, 2H), 2.16 (s, 3H), 2.25 (s, 3H), 3.25 (hr s, 2H), 3.34 (t, J= 6.5 Hz, 2H), 3.46 (t, J=
6.9 Hz, 2H), 4.45-4.59 (m, 1H), 6.91 (d, J= 8.8 Hz, 2H), 7.32 (d, J= 8.9 Hz, 2H), 7.36 (d, J
= 7.7 Hz, 1H), 7.43 (t, J= 7.8, 1H), 7.67 (d, J= 7.9 Hz, 1H), 7.70 (s, 1H), 7.89 (s, 1H), 8.50 (hr s, 1H), 8.56 (br s, 1H), 9.64 (hr s, 1H), 10.21 (hr s, 1H). MS (ES+): m/z 473 (M+H)+.
EXAMPLE 232. 3-Bromo-N-isopropyl-benzamide (Intermediate 83) Br [0446] A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 inmol) in DCM (40 mL) was chilled to zero degrees and treated with isopropylamine (0.96 mL, 11.32 mmol).
Reaction was allowed to come to room temperature and stir for 24 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filleted and evaporated to white solids (0.6 g, 66%).
EXAMPLE 233. N-Isopropy1-3-{5-methyl-244-(4-methyl-piperazin-l-y1)-phenylaminol-pyrimidin-4-ylaminol-benzamide (Compound CLII) NH
0 N N'-) N N
CLII
[0447] A mixture of intetinediate 32 (0.1 g, 0.34 mmol), intermediate 83 (0.13 g, 0.54 mmol), Pd2(dba)3 (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067 mmol) and cesium carbonate (0.33 g, 1 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 15 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by HPLC to afford title compound as white solids (0.011 g, 7%).
[0448] NMR (500 MHz, DMSO-d6): 8 1.14 (d, J= 6.7 Hz, 6H), 2.16 (s, 4H), 2.87 (s, 4H), 3.10 (br s, 2H), 3.51 (s, 2H), 4.22 (in, 1H), 6.85 (d, J= 8.8 Hz, 2H), 7.30-7.32 (in, 2H), 7.45 (t, J= 7.8 Hz, 1H), 7.69-7.70 (in, 2H), 7.90 (s, 1H), 7.99 (s, 1H), 8.24 (d, J= 7.7 Hz, 1H), 9.70 (br s, 1H), 9.94 (br s, 1H), 10.2 (br s, 1H). MS (ES+): m/z 460 (M+H)+.
EXAMPLE 234. 3-Bromo-N-tert-butyl-benzamide (Intermediate 84) A.NH
Br [0449] A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (10 mL) was chilled to zero degrees and treated with tert-butylamine (1.2 mL, 11.3 mmol).
Reaction was allowed to come to room temperature and stir for 4 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to amber oil (0.9 g, 94%).
EXAMPLE 235. N-tert-Buty1-3-{5-methyl-244-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-ylaminol-benzamide (Compound CLIII) =
N el NH
0 N = N'-) ,1\1 CLIII
[0450] A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 84 (0.1 g, 0.4 mmol), Pd2(dba)3 (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067 mmol) and cesium carbonate (0.33 g, 1 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 15 mm. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by HPLC to afford title compound as white solids (0.055 g, 35%).
[0451] 1H NMR (500 MHz, DMSO-d6): 8 1.36 (s, 9H), 2.09 (s, 31-1), 2.21 (s, 3H), 2.43 (t, J= 2.8 Hz, 4H), 3.00 (t, J= 2.8 Hz, 4H), 6.74 (d, J= 9.1 Hz, 2H), 7.35 (t, J=
7.9 Hz, 1H), 7.44-7.48 (m, 3H), 7.67 (s, 1H), 7.85 (s, 1H), 7.88-7.92 (m, 2H), 8.36 (s, 1H), 8.74 (s, 1H).
MS (ES+): ni/z 474 (M+H)+. =
EXAMPLE 236. 5-Methyl-N244-(4-methyl-piperazin-l-y1)-phenyll-/V4-(3-piperidin-0-pheny1)-pyrimidine-2,4-diatnine (Compound CLIV) HN '1\1 NI') N
CLIV
[0452] A mixture of inteanediate 32 (0.08 g, 0.27 mmol), 4-(3-bromo-phenyl)-piperidine (0.084 g, 0.35 mmol), Pd2(dba)3 (0.025 g, 0.027 mmol), Xantphos (0.031 g, 0.054 mmol) and cesium carbonate (0.26 g, 0.81 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 15 min. Reaction vessel was then centrifuged down and decanted. Solvents then evaporated and resulting residue was purified by HPLC to afford title compound as white solids (0.007 g, 6%).
[0453] IHNMR (500 MHz, DMSO-d6): 6 1.74-1.79 (m, 3H), 2.09 (s, 3H), 2.21 (s, 3H), 2.43 (t, J= 2.8 Hz, 4H), 3.00 (t, J= 2.8 Hz, 4H), 6.76 (d, J= 9.1 Hz, 2H), 6.90 (d, = 7.7 Hz, 1H), 7.24 (t, J= 7.9 Hz, 1H), 7.47-7.53 (m, 3H), 7.68 (d, J= 8.2 Hz, 1H), 7.82.(s, 1H), 8.18 (s, 1H), 8.67 (s, 1H). MS (ES+): in/z 458 (M+H)+.
EXAMPLE 237. 4-(3-{5-Methy1-2-f4-(4-methyl-piperazin-1-y1)-phenylaminol-pyrimidin-4-y1aminol-benzenesulfony1)-piperidine-1-carboxylic acid benzyl ester (Intermediate 85) 0)N 411) NH rN
00 õ.),, N f\L`) jj.N
[0454] A mixture of intermediate 32 (0.17 g, 0.58 mmol), 4-(3-bromo-benzenesulfony1)-piperidine-1-carboxylic acid benzyl ester (0.28 g, 0.64 mmol), Pd2(dba)3 (0.053 g, 0.058 mmol), Xantphos (0.067 g, 0.12 mmol) and cesium carbonate (0.57 g, 1.74 mmol) were suspended in dioxane (8 mL) microwaved at 160 C for 15 min. Reaction vessel was then centrifuged down and decanted onto ice. Yellow solids collected, dried and used without further purification (0.4 g, 100%).
EXAMPLE 238. 5-Methyl-N2-1-4-(4-methyl-piper azin-l-y1)-ph env"! j3-(piperidine-4-sulfony1)- phenyl] pyrimidine-2,4-diamine (Compound CLV1 NH
N i\L`) N N
CLV
[0455] A stirring solution of intermediate 85 (0.17 g, 0.26 mmol) in DCM (15 mL) was treated with 1M BBr3 in DCM (2 mL, 2 mmol). After 4 h, reaction was quenched by slow addition of Me0H (4 mL) followed by removal of solvents. Residue purified by HPLC to provide title compound as purple powder (0.008 g, 6%).
[0456] Ill NMR (500 MHz, DMSO-d6): 8 1.31-1.40 (m, 2H), 1.75 (d, J= 10.8 Hz, 2H), 2.12 (s, 3H), 2.21 (s, 3H), 2.36-2.41 (m, 2H), 2.44 (t, J= 4.9 Hz, 4H), 2.95 (d, J = 12.5 Hz, 2H), 3.02 (t, J- 4.9 Hz, 4H), 3.24 (tt, J= 11.7 Hz, J= 3.8 Hz, 1H), 6.81 (d, J= 9.0 Hz, 2H), 7.44 (m, 3H), 7.56 (t, J= 8.0 Hz, 1H), 7.90-.7.91 (m, 2H), 8.49 (d, J= 7.6 Hz, 1H), 8.60 (s, 1H), 8.74(s, 1H). MS (ES+): m/z 522 (M+H)+.
EXAMPLE 239. tert-Butyl 444-(4-(1H-indo1-4-ylamino)-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-l-carborylate (Intermediate 86) HN
=
NH
() I
N
86 NyO
[04571 A mixture of 4-bromo-1H-indole (41 !AL, 0.33 mmol), intermediate 42 (131 mg, 0.33 mmol), Pd2(dba)3 (30 mg, 0.03 mmol), Xantphos (60 mg, 0.10 mmol) and cesium carbonate (428 mg, 1.31 mmol) in dioxane (3 mL) was irradiated in the microwaved at 160 C for 20 min. The reaction mixture was cooled to room temperature and filtered rinsing with DCM. The filtrate was concentrated and purified by gradient flash chromatography (0-15% Me0H in DCM) to afford the title compound as a white solid (30 mg, 17%).
EXAMPLE 240. M-(1H-Indol-4-y1)-5-methyl-N2-(4-(piperidin-4-yloxy)phenyppyrimidine-2,4-diamine (Compound CLVI) HN
()) I
N MP' NH
CLVI
[0458] A mixture of intermediate 86 (27 mg, 0.05 mmol) in 30% TFA/DCM (1 mL) was stirred for 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC. The resulting fractions were concentrated in vacuo to obtain the TFA
salt of the title compound as a tan solid (11 mg, 43%).
[0459] 1H NMR (500 MHz, DMSO-d6): 6 1.71-1.77 (m, 2H), 1.98-2.06 (m, 2H), 2.22 (s, 3H), 3.03-3.12 (m, 2H), 3.19-3.27 (m, 2H), 4.44-4.53 (m, 1H), 6.34-6.37 (m, 1H), 6.64 (br d, J= 8.3 Hz, 2H), 7.08 (t, J= 7.2 Hz, 3H), 7.14 (t, J= 7.8 Hz, 1H), 7.36 (t, J=
2.7 Hz, 1H), 7.39 (d, J= 8.1 Hz, 1H), 7.84 (s, 1H), 8.48 (br s, 1H), 8.55 (br s, 1H), 9.85 (br s, 1H), 9.98 (br s, 1H), 11.27 (s, 1H).
EXAMPLE 241. 2-Chloro-N-12-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-5-01-5 (3-trifluoromethyl-benzoylamino)-benzamide (Compound CL VII) I
-N N
CL VII
[0460] A mixture of 3-bromopyridine (379 mg, 2.4 mmol), 4-amino-2-chloro-5-methylpyrimidine (287 mg, 2.0 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol) and cesium carbonate (975 mg, 3.0 mmol) in dioxane ( 15 mL) was heated under refluxed for 1 h under argon. The solvent was removed and the residue on purification by HPLC gave an intermediate, 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine as yellow solid (252 mg, 57%). For second Buckwald, a mixture of 2-chloro-5-methyl-N-(pyridin-3-yOpyrimidin-4-amine (80 mg, 0.36 mmol), 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (74 mg, 0.34 mmol), Pd2(dba)3 (3.2 mg, 0.003 mmol), xantphos (4.2 mg, 0.007 mmol) and cesium carbonate (234 mg, 0.72 mmol) in dioxane ( 5 mL) was heated under refluxed for 1 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as light brown solid (28 mg, 20%).
[0461] 1H NMR (500 MHz, DMSO-d6): 8 1.85-1.95 (m, 2H), 2.0-2.09 (m, 2H), 2.18 (s, 3H), 3.09-3.18 (m, 2H), 3.55-3.65 (m, 4H), 4.27 (dd, J= 5.2, 4.7 Hz, 2H), 6.94 (d, J= 8.9 Hz, 2H), 7.35 (d, J= 8.9 Hz, 2H), 7.50 (dd, J= 8.2, 4.8 Hz, 1H),7.92-7.96 (m, 1H), 8.08-8.15 (m, 1H), 8.45 (dd, J= 4.8, 1.4, 1H), 8.84, 9.75, 9.85, 10.24 (4 br s, 1H
each). MS (ES+): m/z 329 (M+H)+.
EXAMPLE 242. N2-(4-(2-(pyrrolidin-l-yl)ethoxy)phenyl)-5-methyl-M-(3-(trifluoromethoxy)phenyl) pyrimidine-2,4-diamMe (Compound CLVIII) F3C,o NH
00) C)NI\D
N N
CL VIII =
[0462] A mixture of 1-bromo-3-(trifluoromethoxy)benzene (241 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane ( 15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue on purification by HPLC gave an intermediate, 2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amineas brown solid (260 mg, 85 %). A mixture of this inteimediate (100 mg, 0.33 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (67 mg, 0.33 mmol) in glacial acetic acid (5 mL) was heated under refluxed for 3 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as white solid (11 mg, 7 %).
[0463] 1H NMR (500 MHz, DMSO-d6): 5 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.51-2.55 (m, 2H, superimposed with solvent peak), 2.75 (t, J= 5.9 Hz, 2H), 3.25-3.34 (m, 2H, superimposed with water peak), 3.99 (t, J= 5.9 Hz, 2H), 6.79 (d, J= 8.9 Hz, 2H), 6.98 (d, 1=
8.0 Hz, 1H), 7.40 (dd, J= 7.6, 7.4 Hz, IH), 7.50 (d, J= 8.9 Hz, 2H), 7.76 (br s, 1H), 7.87 (d, J= 8.4 1H), 7.90, 8.31, 8.41, 8.84 (4 s, 1H each). MS (ES+): in/z 474 (M+H)+.
EXAMPLE 243. N2-(4-(2-(pyrrolidin-1-yflethoxy)pheny1)-N444-ehloro-3-(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine (Compound CLIX) ci N
N N
CLIX
[0464] A mixture of 4-bromo-1-chloro-2-(trifluoromethypbenzene (259 mg, 1.0 mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg, 2.0 mmol) in dioxane ( 15 mL) was heated under refluxed for 10 h under argon. The solvent was removed and the residue was purified by HPLC to give an intermediate 2-chloro-N-(4-chloro-3-(trifluoromethyl) phenyl)-5-methylpyrimidin-4-amine as brown solid (200 mg, 62 %). A mixture of this intetmediate (161 mg, 0.5 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (103 mg, 0.5 mmol) in glacial acetic acid (5 mL) was heated under refluxed for 3 h under argon. The crude reaction mixture on purification using HPLC gave the title compound as brown solid (75 mg, 31 %).
[0465] 1HNMR (500 MHz, DMSO-do): 6 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.51-2.55 (m, 4H, superimposed with solvent peak), 2.75 (t, J= 6.0 Hz, 2H), 4.0 (t, J= 5.9 Hz, 2H), 6.79 (d, J= 8.5 Hz, 2H), 7.47 (d, J= 9.0 Hz, 2H), 7.58 (d, J= 9.0 Hz, 2H), 7.93 (s, 1H), 8.01 (d, J
= 2.5 Hz, 1H), 8.22 (d, J= 8.5 Hz, 2H), 8.60, 8.88 (2 s, 1H each). MS (ES+):
tntz 492 (M+H)+.
EXAMPLE 244. IC50 Value Determinations for Jak2 Kinase [0466] The IC50 values for compounds were determined using a luminescence-based kinase assay with recombinant JAK2 obtained from Upstate Cell Signaling Solutions. In white, fiat-bottom, 96-well plates (Nunc) parallel assays were run at room temperature at a final volume of 50 p,L. Each well contained 40 1_1,L of buffer consisting of 40 mM Tris buffer, pH 7.4, containing 50 mM MgCl2, 800 )1M EGTA, 350 jM Triton X-100, 2 mM
mercaptoethanol, 1001_tM peptide substrate (PDKtide; Upstate Cell Signaling Solutions) and an appropriate amount of JAK2 (75 ¨ 25 ng/well) such that the assay was linear over 60 min.
The final concentrations of TargeGen compounds for IC50 value determinations ranged from 1000 to 0.01 )..LM by adding the appropriate amount of compound in 2.5 111, of DMSO; the DMSO present in each assay was constant at 5%. The reaction was initiated by the addition of 10 tL of ATP to a final assay concentration of 3 1.1M. After the reaction had proceeded for 60 min, 50 ).1,L of Kinase-Glo reagent (Promega) was added to terminate the reaction. This solution was then allowed to proceed for an additional 10 min to maximize the luminescence reaction.
[0467] Values were then measured using an Ultra 384 instrument (Tecan) set for luminosity measurements. Two control reactions were also ran: one reaction containing no compound and the second containing neither inhibitor nor peptide substrate.
IC50 values were derived from experimental data using the non-linear curve fitting capabilities of Prism (Version 4; GraphPad Software). The results are shown in Table 1.
TABLE 1. Compounds of the Invention And Their IC Values for Jak2 Kinase , Structure - Name -0 II NH 4-(2,4-Dichloro-5-methoxy-NC-C)---NO 6240 I 1-yl-ethoxy)-phenylamino]-N N pyrimidine-5-carbonitrile CI 40 ci 4-(2,4-Dichloro-5-methoxy-NH
phenylamino)-2-[3-(2-pyrrolidin-NCj, 10500 N
1-yl-ethoxy)-phenylamino]-N 4111 pyrimidine-5-carbonitrile CI 40 ci N4-(2,4-Dichloro-5-methoxy-NH phenyl)-5-methyl-N2-[3 -(2-Me pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine , Structure Name _ 1. N2-(4-(2-(pyrrolidin-1-'o y1-I yl)ethoxy)pheny1)-N4-(3-N 5 -`N methoxypheny1)-5- 52.8 , methylpyrimidine-2,4-diamine N Hydrochloride H
lel 02N NH N2-(4-(2-(pyrrolidin-1-yl)ethoxy)pheny1)-5-methyl-N4-61.1 1\ N (3-nitrophenyl)pyrimidine-2,4-I ),. diamine Hydrochloride r H
. N4-(4-Methoxy-phenyl)-N244-[4 NH (2-pyrrolidin-1-yl-ethoxy)-)-i N 401 (:)-NLD phenyq-pyrimidine-2,4-diamine NN trifluoroacetate H
0 ei 4-[4-(4-Methoxy-phenylamino)-NH 9 i----\ pyrimidin-2-ylaminc]-N-(2-pyrrolidin-l-y1-ethyl) 10700 1 benzenesulfonamide N N 0 0 H trifluoroacetate H
04-[4-(3-Methoxy-pheny1amino)-9 r--\\ pyrimidin-2-ylaminc]-N-(2-pyrrolidin-l-yl-ethyl)- 638 L'i N .1\1.1\1-/
0 H benzenesulfonamide N N 410 trifluoroacetate <0 40 o NH N4-Benzo[1,3]dioxo1-5-y1-5-methyl-N244,-(2-pyrrolidin-1-yl-N el C)NO 87.2 i ethoxy)-phenyl}-pyrimidine-2,4-N diamine trifluoroacetate H
NH
4-[4-(4-Hydroxy-phenylamino)-9 pyrimidin-2-ylamino]-N-(2-N
)1\1 el .,NN pyrrolidin-l-yl-ethyl)-I o H benzenesulfonamide N
H
Structure Name JAK2 HO NH
3-(2-(4-(2-(pyrrolidin-1-ypethoxy)phenylamino)-5-NLsi N 0 0,--,N9 methylpyrimidin-4-ylarnino)phenol Hydrochloride .-N N
H
HO NH 444-(3-Hydroxy-phenylamino)-II 0 pyrimidin-2-ylaminoi-N-(2-'N N pyrrolidin-l-yl-ethyl)- 3620 N
1 0 H benzenesulfonamide '1\r H trifluoroacetate N N-Methy1-3- {5-methy1-2-{4-(2-NH
pyrrolidin-l-yl-ethoxy)-0 --...õ..--L, N Am 0.õ.....õ----,0 phenylaminoi-pyrimidin-4-ylaminol-benzamide H
C, Op -,0 NH N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N244-(2-7.96 pyrrolidin-l-yl-ethoxy)-phenyll-N N pyrimidine-2,4-diamine H
/ N
I
N2-(4-(2-(pyrrolidin-1-NH
yl)ethoxy)pheny1)-N4-=N N Si IC)'== N\ (isoquinolin-l-y1)-5-i methylpyrimidine-2,4-diamine ' H
NNN I. NH N4-(3-Dimethylamino-phenyl)-5-I methyl-N244-(2-pyrrolidin-1-yl- 19.7 0 (:)------NLD ethoxy)-phenyll-pyrimidine-2,4- .
i diamine 'N N
H
CI NH 4-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-5-N 411 67.5 methylpyrimidin-4-ylamino)-2-I ), -.N.-- N chlorobenzonitrile Hydrochloride H
Structure Name N2-(4-(2-(pynolidin-1-40 NH yl)ethoxy)pheny1)-5-methyl-N4-N (naphthalen-1-yl)pyrimidine-2,4- 20 N diamine Hydrochloride CI is CI NH
N4-(3,4-Dichloro-phenyl)-5-methyl-N244-(2-pyrrolidin-1-yl-N 0,-,No ethoxy)-phenyll-pyrimidine-2,4- 25'7 diamine CIO AI
NH N4-(4-Chloro-3-methoxy-pheny1)-5-methyl-N2-(3-15.8 N NH piperazin-l-ylmethyl-pheny1)-NN =pyrimidine-2,4-diamine =
HN el NH
N2-(4-(2-(pyrrolidin-1-ypethoxy)pheny1)-N4-(1H-indol-19.2 N NO 4-y1)-5-methylpyrimidine-2,4-NNSdiamine Hydrochloride = N-(4-(2-(pyrrolidin-1-702.0 yl)ethoxy)pheny1)-4-N
I benzylpyrimidin-2-amine N N
CI
4111 NN2-(4-(2-(pyrrolidin-l-ypethoxy)pheny1)-N4-(4-chloro-3-methoxypheny1)-N4,5- 4900 dimethylprimidine-2,4-diamine N N trifluoroacetate C I oil N4-(4-Chloro-pheny1)-5-methyl-N H N2-[4-(2-pyrrolidin-1-yl-ethoxy)-N phenyll-pyrimidine-2,4-diamine 18'2 N trifluoroacetate Structure Name CI Ai =() WI NH 2- {4- [4-(4-Chloro-3-methoxy-phenyl amino)-5-methyl-9.14 N ()o H pyrimidin-2-y1amino]-phenoxY) N N ethanol 1.1 NH 5-Methyl-N4-phenyl-N2-{4-(2-pyrrolidin-l-yl-ethoxy)-phenyl]- 16.7 pyrimidine-2,4-di amine N
N2-(4-(2-(pyrroli din-1 -NH
ypethoxy)pheny1)-5-methyl-N4- 35.7 N p-tolylpyrimidine-2,4-diamine NN Hydrochloride CI
N2-(4-(2-(pyrrolidin-1 -NH ypethoxy)pheny1)-N4-(4-chloro-3-methylpheny1)-5- = 12.4 N methylpyrimidine-2,4-di amine N Hydrochloride CI
N4-(4-Chloro-3-fluoro-pheny1)-F NH 5-methyl-N2-[4-(2-pyrrolidin-1-40.1 N 1(:).N= 0 yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine CI
1.1 N4-(4-Chloro-3-methoxy-0 NH pheny1)-5-methyl-N2-(4-morpholin-4-ylmethyl-pheny1)- 13.3 N
I pyrimidine-2,4-di amine N trifluoro acetate S
NH N4-B enzo [b]thiophen-5-y1-Nethoxy)-phenyl]-pyrimidine-2,4- 28.5 N = I diamine Structure Name N4-B enzo [bithi ophen-3 -y1-5-S
NH methyl-N244-(2-pyrrolidin-l-yl- /9.4 ethoxy)-pheny1l-pyrimidine-2,4-N N\D
I= diamine N
Cl NH N4-(3 -Chloro-pheny1)-5-methyl-N2-[4-(2-pyrrolidin-1 -yl-ethoxy)- 20.8 Ll\I (31\11,D
I=N phenyl] -pyrimidine-2,4-di amine 2-Chloro-N-1244-(2-pyrro1idin-N NH 1-yl-ethoxy)-phenyl amino] -pyrimidin-5-y1 -5-(3- 304 N = C'NtsD
tri fluoromethyl-b enzoylamino)-N N benzamide O N4-(4-Fluoro-3 -methoxy-NH = phenyl)-5-methyl-N2-[4-(2-N 14.8 4111 (:)' pyrrolidin-l-yl-ethoxy)-phenyl]-pyrimidine-2,4-di amine '1\1 0-7\
N4-B enzo [1,3] dioxo1-4-y1-5-NH methyl-N244-(2-pyrrolidin-1-yl-16.9 ethoxy)-phenyl]-pyrimidine-2,4-N diamine N
Cl Ai N4-(4-Chloro-3 -methoxy-NHpheny1)-5-methyl-N2-(3-9.52 piperazin-1-yl-pheny1)-N
pyrimidine-2,4-diamine N N
F31/4, NH N2-(4-(2-(pyrrolidin-1-ypethoxy)pheny1)-N4-(3-N 17.6 N '`NO (trifluoromethyl)pheny1)-5-JL, methylpyrimidine-2,4-di amine '.1\1 ' JAK2 Structure Name 1050 , N2-(4-(2-(pyrroli din-1 -NH yl)ethoxy)pheny1)-N4-(4-(trifluoromethyl)pheny1)-5- 39.8 N"- 0 i methylpyrimidine-2,4-di amine N hydrochloride H
CI isN4-(4-Claloro-3-methoxy-N
43 NH phenyl)-5-methyl-N2-(4-pyrazol- 18.9 O
-N 1-ylmethyl-pheny1)-pyrimidine-NN 2,4-diamine H
r, 0N2-(4-(2-(pyrrolidin-1-Y NH
' yl)ethoxy)pheny1)-5-methyl-N4-(3- 20.7 CF 0..,,,/,..0 (trifluoromethoxy)phenyl)pyrimi N dine-2,4-diarnine Er -CI 0N2-(4-(2-(pyrrolidin-l-F3C NH yl)ethoxy)pheny1)-N4-(4-chloro-23.4 0 C)NO 3 -(trifluoromethyl)pheny1)-5-methylpyrimidine-2,4-diamine , N N
H
4110 N4-(3-Methoxy-2-methyl-.
0 NH pheny1)-N244-(2-pyrrolidin-l-yl- 371 C3'-'''"' NO ethoxy)-phenyl]-pyiimidine-2,4-N----,I N di amine H _ a 0 NH
N4-(4-Chloro-3 -methoxy-O NH 0õ0 phenyl)-5-methyl-N2-[4-N 4111 \S' (piperidine-4-sulfony1)-phenyll-N N
pyrimidine-2,4-diamine -,,,,,,.
H
CI 0-cto reoth- 3yl_ ...Ne2t h._ [0474_ ..
-' 5 0 NH r'l\la pNh e417). (y41)-.5 410 NI') i } methyl-pip erazin-1-y1)-phenyll-pyrimidine-2,4-diamine 'N. re" N
H J
Structure Name 1050 .
_ ci 0N4-(4-Chloro-3-methoxy-0 NH 0 phenyl)-5-methyl-N2-(4-N I 4110 N morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine N N
H
CI 0N4-(4-Chloro-3-rnethoxy-0 NH In phenyl)-5-methyl-N2-(4-pyrazol- 35.3 N 0 1-yl-pheny1)-pyrimidine-2,4-I
l\ N
), diamine trifluoroacetate 'r H
CI 0N4-(4-Chloro-3-methoxy-0 NH phenyl)-5-methyl-N2-(4-35.3 1 y piperidin-1-yl-pheny1)-N-N pyrimidine-2,4-diamine H
CI 40N4-(4-Chloro-3-methoxy-.0 NH phenyl)-5-methyl-N244-(4-`)IN el I N--.- methyl-piperazin-l-ylmethyl)-'N'N LN'. phenyfl-pyrimidine-2,4-diamine H
HN \
N4-(1H-indo1-4-y1)-5-methy1-411 NH r.I\I N2-(4-(4-methylpiperazin-1- 9.53 N'-'-j yl)phenyl)pyrimidine-2,4-'Li N =
I diamine Hydrochloride N N
H
CI 0N4-(4-Chloro-3-methoxy-0 NH 'NH phenyl)-5-methyl-N2-(4-6.15 N piperazin-1-yl-pheny1)-NN pyrimidine-2,4-diamine H
CI Oil N4-(4-Chloro-3-methoxy-0 NH pheny1)-5-methyl-(piperidin-4-yloxy)-phenyl]-N N 4.14 pyrimidine-2,4-diamine ,, NH
H
Structure Name H2N 4III NH (--,N- 3- {5-Methy1-2- [4-(4-methy1-0 -,,,-1,.. .4.bi N .N ) piperazin-1-y1)-phenylamino]- 23 1 --y pyrimidin-4-ylamino} -benzamide N IRPIP
H
s l 0 3- {5-Methy1-244-(4-methyl-H2N NH r---N- piperazin-1-y1)-phenylamino]-N 13.6 pyrimidin-4-ylamino} -benzenesulfonamide .-N N
H
CI lis N4-(4-Chloro-3-methyl-pheny1)-NH NH 5-methyl-N2-[4-(piperidin-4- 8.41 N 410 (3'' yloxy)-methyl.
-pyrimidine-2,4-N(,,N
.,-. ,j di amine ..,,,, H
ti? NH N di N-(3- {5-Methy1-244-(piperidin-.141W-H 4-yloxy)-phenylaminci-C)'.' pyrimidin-4-ylatninol-phenyl)-N,N NH aeetami de H _.
' NH .õ,.---,,N,--- N4-B enzo [1,3] dioxo1-4-y1-5-methyl-N2 44-(4-methyl-14.2 CImil N piperazin-l-y1)-phenyll-apyrimidine-2,4-di amine N N
H
CI
N4-(4-Chloro-3-trifluoromethyl-F3C (1P11 NH phenyl)-5-methyl-N2-[4- 11.4 NH 410 0------N-. (piperi din-4-yloxy)-phenyli -N
1 ,2LN
. pyrimi dine-2,4-di amine -,_, 'N , H
HN \
Ci N4-(7-ehloro-1H-indo1-4-y1)-5-SO NH '' methyl-N2 -(444-methylpiperazin-1- 5.36 N) yl)phenyl)pyrimidine-2,4-diarnine N.- N
H _ , Structure Name 0'..NH
le N-(2-Methyl-3-{5-methyl-2-[4-(piperidin-4-yloxy)-NH phenylamino]-pyrimidin-4-N ylaminol-pheny1)-acetamide ,, JL N N NH
H
5-methyl-N4-(2,3-1 dimethylpheny1)-N2-(4-.\%-- NH
(piperidin-4- 4.38 0.,_,Th yloxy)phenyl)pyrimidine-2,4--, r\r N VI NH diamine Hydrochloride H
4111NH 5-methyl-N4-(3,5-dimethylpheny1)-N2-(4-(piperidin-4- 37.2 N =N N ...' 1 .., yloxy)phenyl)pyrimidine-2,4-diamine hydrochloride N' a 0-H
si 1 I.
N N NH r----N 1-(3-{5-Methy1-244-(4-methyl-H H =,:*N . N piperazin-l-y1)-phenylaminoi-63.6 pyrimidin-4-ylaminol-phenyl)-3-N N phenyl-urea H
CI ,,. N4-(4-chloro-3,5-1 , dimethylpheny1)-5-methyl---(4-(4-methylpiperazin-1- 38 =)'=1 N a 1\1.') yl)phenyl)pyrimidine-2,4-diamine Hydrochloride N
H
0 NH N4-(3-tert-butylpheny1)-5-r-N- methyl-N2-(4-(4-1\1') methylpiperazin-1- 4.7 -1NN--. yl)phenyl)pyrimidine-2,4-N
diamine Hydrochloride ________________________________________________________________________ , Structure Name H 0 si . N-Methyl-3-{5-methy1-2-[4-(4--. N,Il NH N-methyl-piperazin-l-y1)-phenylamino]-pyrimidin-4-IN N 16.1 .L ylamino}-benzenesulfonamide -N-H
1 0 el N 1, NH (NV N,N-Dimethy1-3-{5-methy1-2[4-.- -(4-methyl-piperazin-1-y1)-6 N 9.5 tI 001 ylaminol-benzenesulfonamide N N phenylamino]-pyrimidin-4-H
HN \
5-methyl-N4-(7-methy1-1H-S NH ,-----...N...-- indo1-4-y1)-N2-(4-(4-methylpiperazin-1- 3.84 N
N N 40) NN) yl)phenyl)pyrimidine-2,4-tdiamine Hydrochloride ---H
''...,-7.
N4-(3-tert-butylpheny1)-5-I methyl-N2-(4-(piperidin-4-..-i).---NH 2.73 yloxy)phenyl)pyrimidine-2,4-diamine Hydrochloride 'N.,,,-N N NH
H
.
40 N4-(3,5-dimethoxypheny1)-5-NH methyl-N2-(4-(piperidiri-4-yloxy)phenyl)pyrimidine-2,4-i diamine trifluoro acetate ==N,,.-NH
H
0 a F3c N1 N N. NH ,----N. 1-(3-{5-Methy1-244-(4-methyl-H H
ah 1\1) piperazin-1-y1)-phenylaminol-pyrimidin-4-ylammol-pheny1)-3--"N N 11-11F (3-trifluoromethyl-pheny1)-urea H
Structure Name 0 0.,õ
411N 2-Methy1-3- {5-methyl-2-{4-(4-methyl-piperazin-l-y1)-NH 27.8 phenylaminol-pyrimidin-4-N ylaminol-benzoic acid ethyl ester N
N 2-Methyl.-3 {5-methyl-2-{4-(4-NH
phenylamino]-pyrimidin-4-N 1\1) ylaminol-benzamide HN
N4-(1H-indo1-4-y1)-5-methyl-NH N2-(4-(piperidin-4-4.27 yloxy)phenyl)pyrimidine-2,4-I diamine trifluoroacetic acid salt 1\1 N
N2-(4-(2-(pyrrolidin-1-40 yl)ethoxy)pheny1)-N4-(3-tert-NH butylpheny1)-5- 6.71 methylpyrimidine-2,4-diamine N-)'N 0-,-No =Hydrochloride N
N2-(4-(2-(pyrrolidin-l-Sypethoxy)pheny1)-N4-(4-(3-tert-NH butylphenylamino)-5-N="¨\ methylpyrimidin-2-y1)-5-methylpyrimidine-2,4-diamine Nr NN N Hydrochloride 5-Methyl-N4-(2-methyl-3-NH trifluoromethyl-pheny1)-N244-52.9 (piperidin-4-yloxy)-phenyli-PYrimidine-2,4-diamine N
Structure Name H2N.C)" SI 3- {5-Methy1-244-(2-pyrrolidin-NH 1-yl-ethoxy)-phenylaminol-72.2 0 -..,-LN 0 0.õ.õ---.. 0 pyrimidin-4-ylamino } -j..N. N benzenesulfonamide H
Y HN,g el N-Isopropyl-3- {5-methy1-244-ii NH r-N- , (4-methyl-piperazin-1-y1)-0 ,,I.,, N.,,.) 11.8 phenylamino] -pyrimidin-4-1 N is, ylamino} -benzenesulfonamide N N
H
0 lel HN4 N-tert-Butyl-3- {5-methy1-244-..,--..N.---ii NH (4-methyl-piperazin-1-y1)-6.06 0 Nõ,1 1 phenylamino]-pyrimidin-4-ylamino} -benzenesulfonamide N-- N
H
\ / 5-Methyl-N2-[4-(4-methyl-piperazin-l-y1)-phenyll-N443-IP NH õ-----...N.--(pip eridine-l-sulfony)-phenyl] - 24.8 N- pyrimidine-2,4-di amine ..eL N Hydrochloride H .
...--.1-SLN
\ 5-Methyl-N2-[4-(4-methyl-piperazin-1-y1)-phenyl] -N443 -S NH rN- (2-methyl-pip eri dine-1- sulfony)- 33.5 phenyl] -pyrimidine-2,4-diamine Hydrochloride .N ''N
H
NH
N4-(3-Methanesulfony1-4-Ii r---N-methyl-pheny1)-5-methyl-N244-0 N.,._,--1 160 I 11 0 (4-methyl-piperazin-l-y1)-phenyl] -pyrimidine-2,4-diamine `N N
H
Structure Name NI el NH N-Cyclohexy1-3- {5-methyl-2-[4-- T, (4-methyl-pip erazin-l-y1)-0 0 L.N 0 rt\I
N,,,..) phenyl amino] -pyrimidin-4- 39.4 1 ,[,. ylamino } -benzenesulfonamide '-' Nr N
H
-1) 0 (...N. N,N-Diethyl-3- {5-methyl-2-[4-NH
0 , N .,) (4-methyl-piperazin-l-y1)-60.3 1 y 0110 phenylamino] -pyrimidin-4-N N ylamino } -benzenesulfonamide ' H
.F3 4111 N4-(3 -(trifluoromethyl)-2-methylpheny1)-5-methyl-N2-(4-NH rN.- (4-methylpip erazin-1- 87.1 yl)phen yl)pyrimidine-2,4-I
N N
diamine hydrochloride `r H
ON 01 (3- 15-Methy1-244-(pip eridin-4-NH
yloxy)-phenylamino]-pyrimidin-N0 (31'`-- 4-ylamino} -pheny1)-pyrrolidin-1-\1 N NH * yl-methanone -.,.
.1 H
H N-Cyclopenty13- {5-Methyl-2-[4-1110(4-methyl-pip erazin-l-y1)-NH .õ0õ----..N.-, phenyl amino] -pyrimidine-4- 19.8 1\1) yl amino } -benzenesulfonarnide '...)., Hydrochloride N N
H
0 ,c------0z-s/LN
\---- 5-Methyl-N2-[4-(4-methyl-LIP piperazin-l-y1)-phenyl]
NH __.----..N.--(pyrrolidine-l-sulfony)-pheny1]- 17.1 N) pyrimidine-2,4-diamine i Hydrochloride leNNI
H
Structure Name o,-----,,õ
1.N,0,, ifti NH N-piperazin-1-y1)-pheny11-N443-5-Methyl-N244-(4-methyl-II
20.7 0 --....õ,--1,-z,N 0 N..,,s,......--(morp1o1ine-4-su1fony1)-pheny1i -N
1 pyrimidine-2,4-di amine =N
H _ NH r..N. N-Isopropyl-371 5 -methy1-2-{4-(4-methyl-piperazin-1 -y1)-0 N.) 541 N
phenylarnino] -pyrimidin-4-N
..,.. N 0 ylaminol-benzamide H
I
0=S=0 methy1pip erazin-1 el ......----...N. 5-methyl-N2-(4-(4--yl)pheny1)-NH N4-(3- 215 '-)*1 N . NI') (met hylsulfonyl)phenyl)pyrimidi i ne-2,4-diamine 'N N
H
A.N
NH
N-tert-Butyl-3- {5-methy1-244-ry 0 I\12 (4-methyl-pip erazin-1 -y1)-L.'N
0 phenyl amino] -pyrimidin-4-jyl amino 1 -benzami de N N
H
.
0=S=0 5-methyl-N2-(4-(4-SiNH methylpiperazin-1-yl)pheny1)-N4-(3- 8 r N - (propylsulfonyl)phenyl)pyrimidin 0 N`) e-2,4-di amine i ..
'N N
H
5-Methyl-N2-[4-(4-methyl-42.5 N- _y1)-pheny1]-N4-(3-N4 pip erazin-1 HN 42 .5 N'N 0 N) piperidin-4-yl-phenyl)--.,N *N pyrimi dine-2,4-di amine H
Structure Name _ '''....../
HN N-tert-Butyl-345-methy1-2-(4-,11 S NH morpholin-4-ylmethyl-1 I 12.5 0 ii 0 N phenyl amino)-pyrimidin-4-NN 0 ylaminol-benzenesulfonamide H
r, /0 1---=S-/--NH
N-tert-Butyl-345-methy1-2-(4-piperazin-l-yl-phenyl amino)-NH rNH pyrimidin-4-ylaminol- 7.59 -)..1 N . N') benzenesulfonamide ' Hydrochloride N N
H
uN
Y N443 -(2,5-Dimethyl-pyrrolidine-1-sulfony1)-phenyl] -5-methyl-NH r-N- N244-(4-methyl-piperazin-l-y1)- 18.8 e phenyllpyrimidine-2,4-di amin N 0 N') Hydrochloride 1 1,.
N N
H
G'H
\<- N-tert-Butyl-3 -(2- {44442-S NH OH hydroxy-ethyl)-piperazin-l-yl] --,N phenyl amino } 45-methyl-7.09 N.,,) pyrimidin-4-ylamino]-"N
I ),, benzenesulfonamide ' NN 0 Hydrochloride H
`,.----HN el NH N-tert-Butyl-345-[5-2-(4-,cil ii r----- pyrazol-1 -yl-phenylamino)-,,,I., / pyrimidin-4-ylaminoi -0 40 N, 1 '`I\I N
.N.A'N benzenesulfonamide H
\./
HN N-tert-Butyl-345-[5-2-(6-, III
IT NH (NH
pip erazin-l-yl-pyridin-3 -0 NN) yl amino)-pyrimidin-4-ylamino]--,N-- N.------..-z.. b enzenesulfonami de H
Structure Name 2-[4-(3- {5-Methy1-244-(4-NH N methyl-pip erazin-l-y1)-HO phenyl amino] -pyrimidin-4- 8.46 yl amino } -pheny1)-piperidin-1-N N A-ethanol N-tert-Buty1-345-methy1-2-(3-101morpholin-4-ylmethyl-7.06 NH phenyl amino)-pyrimidin-4-yl amino] -b enzenesulfonamide r0 N N
N-tert-Butyl-345-[5-2-(4-HN ,913c* NH pyrazo1-1-ylmethyl-18.6 0 N N phenyl amino)-pyrimidin-4-I [N, yl amino } -b enzenesulfonami de N N
O el HN,g NH N-tert-Butyl-3- {5-methyl-243 -(piperidine-1-sulfony1)-phenyl amino]-pyrimidin-4-N N ylamino } -benzenesulfonamide 0 IP N-tert-buty1-3- f[5-methy1-24 {4-NH
HN [(4-methylpiperazin-1-'S
I
0 yl)methyl]phenyl} amino)pyrimid 29.8 N in-4-N yl] amino } b enzenesulfonamide O NH CF3 N-tert-butyl-3-[(5-methyl-2- {[4-NH
HN
4111 pip erazin-l-y1-3 O N (trifluoromethyl)phenyl] amino } p 22.5 Si yrimidin-4-N yl)amino]benzenesulfonamide &TALC
Structure Name 0 3-[(2- { [4-(4-acetylpiperazin-1-HN , g ? NH CF3 ( N --1C
6 - ).. N ,1 (trifluoromethyl)phenyl] amino } - 35.7 1 11 * 5-methylpyrimi din-4-y1) amino] -... IN( N N-tert-butylb enzenesul fonami de H
r, õ0 'S-NH
`
110 NHN-tert-Buty1-345-methy1-2-(3 -piperazin-1-yl-phenylamino)-pyrimidin-4-ylamino] - 18 \/Li .1. ei benzenesulfonamide Hydrochloride - N-....N1 H
c.,-NH
r, 0'9 NH
=<" N-tert-Butyl-3-(2- {34442-hydroxy-ethyl)-pip erazin-l-yl] -la NH phenylamino } 45-methyl-40.5 pyrimidin-4-ylamino] -i benzenesulfonamide N N N..-.1 Hydrochloride H
IN-'0H
',-../.
141111 N-tert-butyl-3- {[5-methyl-2-( {3 -HN,QH
if NH [(4-methylpip erazin-1 -0 -.,..-L, 'N N. yl) sulfonyl]phenyl ] amino)pyrimi 650 1 ),, el 9 0 din-4-Nr. N S".1\1 yl] amino } b enzenesulfonami de 0N-tert-butyl-3 -[(5-methy1-2- { [4-HN,g 1411) (piperazin-1-L
ylmethyl)phenyl] aminolpyrimidi 4.6 I
n-4--.....õ--0 N N.) L.,----__. NH
yl)amino]benzenesulfonamide = N-- I. N
H
9\ 140 NH N
5-Methyl-N2.-[4-(4-methyl-0 NIr--) pip erazin-l-y1)-phenyl] -N443 -rS 'NN--N el N
HN, eridine-4-sulfon 1 -heny1]-(PiP Y ) 13 pyrimidine-2,4-diamine '1\1 N
H
Structure Name .
5-methyl-N2-(4-(4-,--..Nõ--N el NH methylpiperazin-1-yl)pheny1)-* NN.---- N4-(3-(piperidin-1- 46.3 i 4 yl)phenyl)pyrimidine-2,4-'N.N.N diamine H _ N4-(3-(1H-pyrrol-1-yl)pheny1)-5-al SI NH (N methyl-N2-(4-(4-0 N') methylpiperazin-1- 33.8 -(NN yl)phenyl)pyrimidine-2,4-diamine H
H
NH
rN 3- (5-Methy1-244-(4-methyl-piperazin-l-y1)-phenylaminol-HN., 0 N,,,2 'N-.= --,-'''Ll el pyrimidin-4-ylaminoI-N- 543 piperidin-4-yl-N
H benzenesulfonamide HN-N
\
S NH N4-(1H-indazol-4-y1)-5-methyl-N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-I 1,, diamine Hydrochloride L
H
HN \
Si NH N4-(1H-Indo1-4-y1)-5-methyl-N2-(4-morpholin-4-ylmethyl- 7.42 N alb N'= pheny1)-pyrimidine-2,4-diamine `N*N VI 10 H
HN \
el NH N4-(1H-Indo1-4-y1)-5-methyl-N2-(4-piperazin-l-ylmethyl- 10.1 N 5 N) pheny1)-pyrimidine-2,4-diamine .. A, LNH
N N
H
Structure Name H
>-N-,:s\ NH N-tert-Butyl-3- {5-methyl-2-[4-0 \0 (2-pyrroli din-1 -yl-etho xy)-12.5 401 N.ILD phenyl aminol-pyrimidin-4-N N yl amino } -benzenesulfonamide HO NH
3 -(2-(4-(piperidin-4-yloxy)phenylamino)-5-- C) 51.9 methylpyrimidin-4-ylamino)phenol / NH
CI
N2-(4-(2-(pyrrolidin-l-yl)ethoxy)pheny1)-N4-(7-chloro-HN 1H-indo1-4-y1)-5- 1.16 NN Si NO methylpyrimidine-2,4-di amine Hydrochloride /NH
N2-(4-(2-(pyrrolidin-l-yl)ethoxy)pheny1)-5-methyl-N4-HN (7-methyl-I H-indo1-4- 6.98 -1 yl)pyrimidine-2,4-diamine NN SiHydrochloride / NH
F
N2-(4-(2-(pyn-olidin-l-yl)ethoxy)pheny1)-N4-(7-fluoro-HN 1H-indo1-4-y1)-5- 9.28 NO methylpyrimidine-2,4-di amine N Hydrochloride CI Am o Wi NHN4-(4-Chloro-3-methoxy-NH pheny1)-5-methyl-N2-(6-12.1 N piperazin-1 -yl-pyridin-3 -y1)-NN pyrimidine-2,4-di amine Structure Name SI 544-(4-Chloro-3-methoxy-0 NH 0 0 ("...N phenylamino)-5-methyl-H pyrimidin-2-ylamino]-2- 5.12 N N
piperazin-l-yl-benzoic acid N methyl ester LIP
0 0 544-[4-4-NH ylamino)-5-methyl-pyrimidin-2-ylamino]-2-(2-pyrrolidin-l-yl- 16.4 N '-'NtD
ethoxy)-benzoic acid methyl ester >1\1,,s, NH N-tert-Butyl-3-{5-methyl-244-[4 (piperidin-4-yloxy)-0"0 7.3 Nphenylaminol-pyrimidin-4-I
el NH ylamino}-benzenesulfonamide HN
N4-(1H-Indo1-5-y1)-5-methyl-NH
N2-[4-(piperidin-4-yloxy)-N (:)N1 phenyfl-pyrimidine-2,4-diamine N NH
. H.
ah 0 2- {544-(Benzo[1,3idioxo1-4-NH ylamino)-5-methyl-pyrimidin-2-N
1 ethanol 0¨\
N4-Benzo[1,3]dioxo1-4-yl-N243-NH methoxy-4-(2-pyrrolidin-l-yl-9.34 ethoxy)-pheny1]-5-methyl-N C)NID
=pyrimidine-2,4-diamine '1\1 N
Structure Name H
..õ-N, 410 NH N N-tert-Butyl-3 -[2-(4-imi dazol-1-/A\ [---:----- yl-phenyl amino)-5-methyl-0 0 N 0 1\L' pyrimiclin-4-ylaminoi- 12.3 I benzenesulfonamide .si\( N
H
H
>NH N,,,,s\ el N-tert-Butyl-3 42-(4-imidazol-1 -o' \o ylmethyl-phenylamino)-5-8.42 N N
Y:11 . NZN methyl-pyrimidin-4-ylamino]-benzenesulfonamide H
H
r ..N,./S\ NH ISI N-tert-Butyl-3-{2-[4-(2-hydroxy-ethoxy)-phenyl amino] -5-methyl-,L, 1 1\1 0 CIOH pyrimidin-4-ylamino } - 20.3 c o -:NL N benzenesulfonamide H
\,-0:.-zg-NH
N-tert-Butyl-3- {5-methy1-244-101 NH (4-oxy-morpholin-4-ylmethyl)-48.6 phenyl amino] -pyrimidin-4-0- yl amino 1 -benzenesulfonamide 'LN
N N VI Aki II\1+Th Lo CI it&
N4-(4-Chloro-3-methoxy-o 4-F NH phenyl)-5-methyl-N2-(4-15.2 I N--'. piperazin-1-ylmethyl-phenyl)-I\IN qW1 NH pyrimidine-2,4-di amine ' -,,,, H
H
>N,,,s\ lelNH \)---_,..:N N-tert-Butyl-3-{5-methy1-244-(2-methyl-imidazol-1-y1)-cro 1 1 0 N,/} 34.3 phenyl amino]-pyrimidin-4-yl aminol-b enzenesulfonamide 'µN N
H
H
>N;s\ II N-tert-Butyl-3- IS-methyl-244-[4 NH (2-methyl-imidazol-1-ylmethyl)-21.9 c)/ \(:) '-----'L-H.I 0 Nt...,__I-4N phenylaminol-pyrimidin-4-ylamino}-benzenesulfonamide ..1\1 N
H
, Structure Name H
>N..,/s\ Si NH N-tert-Butyl-3[5-methy1-2-(4-pyridin-4-ylmethyl-0"0 80.7 N
IN 4111 phenylamino)-pyrimidin-4-1\ . N ylaminol-benzenesulfonamide .'r H
H
>- S\
0 NH N-tert-Butyl-345-[5-2-(4-cro = N morpholin-4-yl-phenylarnino)-benzenesulfonamide ,N) 12.1 pyrimidin-4-ylaminoi-'IeN
H
ialli NH'D -(4-(1H-pyrazol-1-yl)pheny1)-1\1 ,I/ N2 N4-(3-tert-butylpheny1)-5- 151 I ), methylpyrimidine-2,4-diamine 'i\r N
H
HN \
CI gib RP N4-(7-chloro-1H-indo1-4-y1)-5-NH
methyl-N2-(4-((piperazin-1-N
N
yl)methyl)phenyl)pyrimidine-2,4-I diamine Hydrochloride -'i\r N 411 NH
H
110 NH 1\1\ N4-(3-tert-butylpheny1)-5-methyl-N2-(4-(2-methy1-1H-38.4 110 Nj imidazol-1-yl)phenyl)pyrimidine-,, N N 2,4-diamine Hydrochloride -`
H
N4-(3-tert-butylpheny1)-5-rN, methyl-N2-(4-(2-methy1-1H-Nd¨ 94.1 N
= 110 1\1*N imidazol-1-yl)phenyl)pyrimidine-2,4-diamine Hydrochloride H
H
N-tert-Buty1-345-methy1-2-(4-NH
[1,2,4]triazol-1-ylmethyl-0"0 ,),, 35.4 jkl., 0 N.N phenylamino)-pyrimidin-4-ylaminol-benzenesulfonamide N N L---:-N
H
Structure Name H
NHI,----_\._ N-t ert-Buty1-3 - { 5-methyI-2- [4-(4-methy1-imidazol-1-y1)-, 0 N 40 N'" phenylamino]-pyrimidin-4- 41.7 i N, N yl amino } -benzenesulfonamide .' H
2,N-Dimethy1-5- f5-methy1-244-[4 .--- N-Is\ NH (2-pyrrolidin-1-y1-ethoxy)-6\0 .-)''1\1 Si -N) phenyl amino} -pyrimidin-4-N*N ylamino } -benzenesulfonamide H
H
s ...N.;, 0 NH N-tert-Buty1-2-methy1-5- {5-1 0/. 4/0 0No methy1-2-[4-(2-pyrrolidin-1-y1-44.4 j,. ethoxy)-phenyl amino] -pyrimi din-\' N N 4-ylamino } -benzenesulfonamide H
H
N,,s \ 1.0 NH iii N-tert-Butyl-345-methyl-2-(4-----N [1,2,4}triazol-1-yl-phenylamino)-6 b ,N)õ Si N,,./,,,,' p yrimidin-4- ylaminol- 41.4 tNN benzenesulfonamide H
-') NH 4111 .Sµ NH N-tert-Buty1-3- {5-methy1-243-(1H-tetrazol-5-y1)-phenylamino]- 55.9 pyrimidin-4-ylamino I-t NN 0 )\1 benzenesulfonatnide H,,N
HN-N
H (11101 N, __N N-tert-Buty1-542-(4-imidazol-1-A\ NH
0 0 N)yl-phenylamino)-5-methyl-88.2 N
N
pyrimidin-4-ylarnino] -2-methyl-b enzenesulfonamide N
H
H
NH N-tert-Butyl-3- {5-methy1-244-(pyrrolidine-1 -earbony1)-0 0 33.5 - 0 0 phenylaminoi -pyrimidin-4-jj, ylamino} -benz enesulfonamide N N
hl CA 02628283 2008-05-01 .
_ JA.K2 Structure Name . 1050 , H
>, N , NH N-tert-Buty1-3- {5-methy1-244-0 0 0 (morpho line-4-carb ony1)-32.9 '-''-)N 0 N phenyl aminoFpyrimidin-4--, N 1-..,..0 y1amino)-benzenesulfonamide " N
H
H
>' S\
40 NH 0 N-tert-Butyl-3- {5-inethy1-244-(pip erazine-1 - carb ony1)-0 "
N ---') phenyl aminoj-pyrimi din-4-L
L. NH Amino} -benzenesulfonamide N
H
NH HN N-tert-Buty1-3- {5-methy1-2-{4--Nõ
,N (1H-tetrazol-5-y1)-phenylaminol-96.7 N
N
N pyrimidin-4-ylamino} -benzenesulfonamide Thq 14111 H
1101 N4-(3-tert-butylpheny1)-5-NH
methyl-N2-(4-(1-moTholinoethyl)- 19.9 phenyl)pyrimidine-2,4-diamine N O0 Hydrochloride li H
>'N `1S, o\ 41111 NH (N'N -..-= 3- {244-(4-Acetyl-piperazin- 1-y1)-phenyl amino1-5-methyl-0 -,,iõ N .,) 18.6 t"11, Spyrimidin-4--ylamino} -N-tert-N.-- N butyl-benzenesulfonamide H
1.1 NH NH N4-(3-tert-butylph eny1)-5-rnethy1-N2-(4-(piperidin-4-20.9 Si , yl)phenyl)pyrimi dine-2,4-diamine Hydrochloride N N
H
>,..N,sis\ * NH N-tert-Butyl-3- {5-methy1-244-(1 -morpholin-4-yl-ethyl)-01-\ 0 , 29.7 i N N phenyl amino] -pyrimidin-4-NN14111 1,,o ylamino } -b enzen esulfon amide H
Structure Name 5-methyl-N4-(2,3-, I dimethylpheny1)-N2-(4-(4-methylpiperazin-l- 16 N
NN yl)phenyl)pyrimidine-2,4-diamine Hydrochloride CI
N4-(4-chloro-2-methylpheny1)-5-NH methyl-N2-(4-(4-N methylpiperazin-1- 15.9 yl)phenyl)pyrimidine-2,4-diamine Hydrochloride 5-methyl-N4-(3,4-N H I dimethylpheny1)-N2-(4-(4-methylpiperazin-1- 16.6 = yl)phenyl)pyrimidine-2,4-N N diamine Hydrochloride EXAMPLE 245. Determination Of Efficacy Of Selected Ccompounds [0468] HEL, CTLL-2 & nonnal human dermal fibroblasts (NHDF) were from the American Tissue Culture Collection Rockville, MD). BaF/3 cells were obtained from DKFZ
Cancer Research Center (Heidelberg, Germany).
[0469] BaF/3, HEL & NHDF cells were grown in RPMI 1640 medium (Gibco BRL, Gaithersburg, MD) supplemented with penicillin, streptomycin, L-glutamine, and 10% fetal bovine serum (FBS). CTLL-2 cells were grown in the same media further supplemented with 20 U/mL recombinant IL-2 (Hoffmann-LaRoche, Nutley, NJ). Plasmid containing the human JAK2 coding sequence was purchased from Invitrogen (Madison, WI). JAK2v617F
cDNA
was generated by using site-directed mutagenesis to introduce the V617F
mutation into the human JAK2 coding sequence followed by verification using two-directional sequencing.
This cDNA was subsequently subcloned into a retroviral vector and transduced into BaF/3 cells. Permanently transduced BaF/3 cells expressing JAK2v617F were selected and maintained with 1 mg/m1 G418. GFP was introduced into this cells by lentiviral transduction using pLenti6-GFP (Invitrogen) followed by selection with blasticidin and confirmation of GFP expression using FACs analysis.
[0470] Cell proliferation assay was performed using the XTT cell proliferation kit according to the manufacturer's instructions (Roche, Alameda, CA). In brief, approximately 2.5 X 103 cells were plated in triplicate into microtiter-plate wells in 100 uL RPMI growth media plus various doses of XLV. After 72 hour incubation twenty microliters of XTT was added to the wells and allowed to incubate for 4-6 hours. The colored fonnazan product that is formed was measured spectrophotometrically using the Vmax spectrophotometer (Molecular Devices, Sunnyvale, CA) at 450 nm with correction at 650 rim. IC50 values were determined using the GraphPad Prism 4.0 software (San Diego, CA), wherefore OD
values were plotted on y-axis (linear scale) and concentration (mM) on the x-axis (log scale). Data was subjected to a non-linear regression fit analysis and IC50 values were detennined as the concentration which inhibited proliferation 50%.
[0471] Proliferation EC50:
HEL ¨ 270 nM
Baf3:JAK2V617F ¨297 nM
Control data: IL-2-induced JAK3-dependent proliferation ¨ 3395 nM
Control data: Normal human dermal fibroblast control ¨ 6487 nM
Apoptosis assays [0472] BaF/3-JAKv617F cells cultured in growth medium (RPMI, 10%FBS, 1 mg/ml and 10 p.g/mlblasticidin) were treated with XLV at 1, 3 and 10 uM for 24 h.
Following harvesting cells by centrifugation at 890 RCF (relative centrifugation force) for 5 mm, genomic DNA was isolated from cell pellets using a DNA isolation kit (Puregen, Chino, CA).
jig genomic DNA of each sample was subjected to 1.2% agarose gel electrophoresis to detect genomic DNA fragmentation (DNA laddering assay). As a control, adherent noinial human dennal fibroblasts (NHDF) cultured in growth medium (Cambrex, Walkersville, MD) at 60% confluence were treated with XLV as described above. Following 2 washes with ice cold PBS, genomic DNA was isolated from the NHDF cells for agarose gel electrophoresis.
Immunoblotting [0473] BaF/3-JAKv617F cells treated with XLV or vehicle control were centrifuged, washed 2X with ice-cold PBS and lysed using RIPA buffer. Protein concentration was determined using the BCA method (Pierce, Rockford, IL) and 100 jig of total cellular protein of each sample in 1X Laemmli buffer were subjected to Western blot analysis.
The protein blot was probed with an anti-phospho-STAT5 (Tyr694/699) (Upstate Biotechnology, Charlottesville, VA), subsequently stripped and re-probed with an anti-STAT5 antibody (Cell Signaling Technology, Danvers, MA). The phospho-STAT5 or STAT5 protein was visualized by the enhanced chemoluminescence method (Pierce). In vivo signaling studies were done in a similar fashion. Briefly, on day 11 after cell injection, animals were orally dosed with either vehicle or 100 mg/kg of XLV. Spleens were harvested 7 h after dosing and quickly homogenized in a FastPrep machine (Qbiogen, Irvine, CA). 100 pg of each spleen homogenate were subjected to Western blot analysis. The protein blot was probed with an anti-phospho-STAT5 (Tyr694/699) and subsequently with an anti-STAT5 antibody and visualized by the enhanced chemolumine,scence method.
FACs analysis of circulating tumor burden [04741 On day 11 after injection of BaF/3-JAK2v617F cell suspension, 1 mL
blood was collected by a terminal cardiac bleeding method from one mouse that received vehicle, moreover, 0.1 mL blood was collected by a non-lethal retro-orbital collection method from mice of each of the three groups dosed with 10, 30 or 100 mg/kg of XLV and pooled together within the dose groups. Blood mono-nucleated cells were isolated by a Ficoll (Sigma-Aldrich, St. Louis, MO) cushion centrifugation method (600 RCF and 30 min). The isolated cells were subjected to FACS analysis to determine the percentage of OFF positive BaF/3:JAK2v617F cells. The results are shown in Figure 1.
Circulating Tumor Model [0475] SCID mice were intravenously injected with BaF/3 cells expressing JAK2v617F and GFP. XLV was dosed orally at the indicated doses beginning 3 days after infusion and ending 20 days after infusion. On day 11 blood was taken from animals in each group and subjected to FACs analysis to determine the percentage of circulating cells which were GFP
positive. In a parallel study animals were treated as described above with the exception that they were given a single 100 mg/kg dose of drug on day 11 followed 4 hours later by sacrifice and analysis of STAT5 phosphorylation in the tumor-bearing enlarged spleen. The results are shown in Figure 2.
Ocular exposure and efficacy data 10476] Exposure data of compounds at 0.1% via eye drop administration:
[0477] On topical dosing of compounds fonnulated as 0.1% doses in 0.2%
tyloxapo1/1%
HPMC/4% Mannitol, exposure levels in found in back of the eye tissues of the mouse are shown at two different time points, namely at 2 h and at 7 h. The efficacy data for selected compounds are shown in Table 2.
Concentration (nM) in mouse ocular tissues following bilateral topical instillation of 0.1% formulation QDX1 Concentration (nM) Formulation concentration for selected compounds Time (hr) retina Sclera/choroid Cornea 0.1% XVII 2 495 6040 8840 0.1% X.XXVI 2 816 7250 7870 0.1% XLIV 2 406 4840 103000 0.1% LXXXII 2 267 2340 69900 0.1% LXXIV 2 2120 6090 45000 EXAMPLE 246. Compound XVII in an Ocular efficacy study in an oxygen-induced retinopathy (OIR) model [0478] Compound XVII was tested using the mouse oxygen-induced retinopathy (OIR) model, in which retinal neovascularization is triggered by cycling mouse pups from normoxia to hyperoxia and then back to normoxia. Litters of C57BL/6 mice were transferred to a hyperoxic environment (70% 02) starting on postnatal day 7 (P7). After 5 days, litters were returned to a nounoxic environment (21% 02), where they were then maintained for an additional 5 days, during which time they received topical applications of either compound XVII or an appropriate vehicle. At the end of this period, retinal whole-mounts were prepared and stained with a fluorescently-labeled lectin (BSL I) that recognizes murine endothelium. Finally, digital images were obtained by fluorescence microscopy and analyzed with an image analysis software program in order to quantify vascular area. In one study, animals dosed with a 0.1% formulation of compound XVII twice daily (bid) showed a 29%
reduction in vascular area as compared to vehicle-treated animals (P<0.05, a=
11-15); in a second study, a 22% reduction was observed (P<0.02, n 6). The results are summarized in Table 3.
Vascular Area % Change vs.
Study # Treatment Group (nun2, mean SD Vehicle Control Vehicle 4.9 1.6 0.1% XVII 3.5 th 0.6 -29%
Vehicle _________________________ 8.3 th 0.8 0.1% XVII 6.4 1.6 -22%
104791 Although the invention has been described with reference to the above examples, the scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.
Claims (143)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound having the structure (A):
wherein:
X is selected from the group consisting of a bond, O, and CH2; Y is selected from the group consisting of a bond and NR9; or X and Y taken together is a bond;
each of R1 and R2 is independently selected from the group consisting of H, C1-unsubstituted alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C14 heterocycle, substituted or unsubstituted C5-C14 aryl, and substituted or unsubstituted heteroaryl; or R1 and R2 taken together is a bond; or R1 and R2 taken together form a moiety selected from the group consisting of (CH2)m, (CH2)r¨S-(CH2)m, (CH2)r¨SO¨(CH2)m, (CH2)r¨
SO2¨(CH2)m, (CH2)r¨NR9¨(CH2)m, and (CH2)r-O¨(CH2)m;
each of p, q, r, n, m is independently an integer having the value between 0 and 6, R9 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, branched alkyl, C1-C6 substituted alkyl, C1-C6 aminoalkyl, and C1-C6 hydroxyalkyl;
G0 is selected from the group consisting of N, O, and CH, with the proviso that if G0 is N, then:
each of R3 and R4 is independently selected from the group consisting of H, C1-alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted C5 -aryl, and substituted or unsubstituted C5-C14 heteroaryl, or R3 and R4 taken together form a moiety selected from the group consisting of (CH2)m, (CH2)r-S-(CH2)m, (CH2)r-SO-(CH2)m, (CH2)r-SO2-(CH2)m, (CH2)r-NR9-(CH2)m, and (CH2)r-O-(CH2)m, or R3 and R4 are taken together with G0 to form an aromatic, heteroaromatic, cyclic or heterocyclic ring system;
with the further proviso that if G0 is O, then:
R3 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, substituted or unsubstituted branched C3-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted C3-C14 heterocyclic connected through carbon or nitrogen, substituted or unsubstituted C5-C14 aryl, and substituted or unsubstituted C5-C14 heteroaryl connected through carbon or nitrogen, with no group R4; or R1 and R3 taken together form a moiety selected from the group consisting of (CH2)m, (CH2)r-S-(CH2)m, (CH2)r-SO-(CH2)m, (CH2)r-SO2-(CH2)m, (CH2)r-NR9-(CH2)m, and (CH2)r-O-(CH2)m;
with the further proviso that if G0 is CH, then:
each of R3 and R4 is independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted C5-aryl, substituted or unsubstituted C3-C14 heterocycle connected through carbon or nitrogen, and substituted or unsubstituted C5-C14 heteroaryl connected through carbon or nitrogen, or R3 and R4 taken together form a moiety selected from the group consisting of (CHR9)r-(CHR9)m-(CHR9)p, (CHR9)r-S-(CHR9)m, (CHR9)r-SO-(CHR9)m, (CHR9)r-SO2-(CHR9)m, (CHR9)r-NR9-(CHR9)m, and (CHR9)r-O-(CHR9)m;
each G is independently N or CR6, or C when bonded to X, provided that not more than two groups G can be N, and each R6 is independent of each other group R6;
R5 is methyl;
each of R6, R7, R8 is independently selected from the group consisting of H, substituted or unsubstituted alkenyl, C2-C6 substituted or unsubstituted alkynyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted cycloalkyl, substituted or unsubstituted C5-C14 aryl, substituted or unsubstituted C5-C14 heteroaryl connected through carbon or a heteroatom, a halogen, CF3, -OCF3, SO2H, SO2(C1-C6 alkyl), heterocycle, SO2-cycloalkyl, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)(C1-C6 alkyl), SO2NH(C3-C6 cycloalkyl), SO2NH-heterocycle, SO2NH(C3-C6 branched alkyl), NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), NO2, CN, CONH2, CONH(C1-C6 alkyl), CON(C1-C6 alkyl)(C1-C6 alkyl), CO(C1-C6 alkyl), CO-heterocycle, COOH, COO(C1-C6 alkyl), NHCO-(C1-C6 alkyl), and NHCONH-aryl, or any 'of R6 and R7 taken together, or R7 and R8 taken together, or R6 and R8 taken together form a moiety independently selected from the group consisting of -HN-CH=CH-, -HN-N=CH-, -HN-N=N-, -O(CH2)n O-, -S(CH2)n S-, -N=CH-S-, -CH=N-O-, -CH=N-S-, -N=CH-O-, -C=N-O-,-CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -O-CH=CH, and -S-CH=CH-;
A is selected from the group consisting of O, NH, N-(C1-C6 alkyl), CH2, S, SO, and SO2;
G1 is selected from the group consisting of CH and N;
G2 is selected from the group consisting of CR7 and N, with each group R7 being independent of every other group R7;
wherein the substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle, for each occurence if any, have one or more substituents selected from the group consisting of hydroxy, alkoxy, mercapto, cycloalkyl, heterocyclic, aryl, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, and sulfuryl;
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers of the compound (A).
wherein:
X is selected from the group consisting of a bond, O, and CH2; Y is selected from the group consisting of a bond and NR9; or X and Y taken together is a bond;
each of R1 and R2 is independently selected from the group consisting of H, C1-unsubstituted alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C14 heterocycle, substituted or unsubstituted C5-C14 aryl, and substituted or unsubstituted heteroaryl; or R1 and R2 taken together is a bond; or R1 and R2 taken together form a moiety selected from the group consisting of (CH2)m, (CH2)r¨S-(CH2)m, (CH2)r¨SO¨(CH2)m, (CH2)r¨
SO2¨(CH2)m, (CH2)r¨NR9¨(CH2)m, and (CH2)r-O¨(CH2)m;
each of p, q, r, n, m is independently an integer having the value between 0 and 6, R9 is selected from the group consisting of H, C1-C6 alkyl, C3-C6 cycloalkyl, branched alkyl, C1-C6 substituted alkyl, C1-C6 aminoalkyl, and C1-C6 hydroxyalkyl;
G0 is selected from the group consisting of N, O, and CH, with the proviso that if G0 is N, then:
each of R3 and R4 is independently selected from the group consisting of H, C1-alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted C5 -aryl, and substituted or unsubstituted C5-C14 heteroaryl, or R3 and R4 taken together form a moiety selected from the group consisting of (CH2)m, (CH2)r-S-(CH2)m, (CH2)r-SO-(CH2)m, (CH2)r-SO2-(CH2)m, (CH2)r-NR9-(CH2)m, and (CH2)r-O-(CH2)m, or R3 and R4 are taken together with G0 to form an aromatic, heteroaromatic, cyclic or heterocyclic ring system;
with the further proviso that if G0 is O, then:
R3 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, substituted or unsubstituted branched C3-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted C3-C14 heterocyclic connected through carbon or nitrogen, substituted or unsubstituted C5-C14 aryl, and substituted or unsubstituted C5-C14 heteroaryl connected through carbon or nitrogen, with no group R4; or R1 and R3 taken together form a moiety selected from the group consisting of (CH2)m, (CH2)r-S-(CH2)m, (CH2)r-SO-(CH2)m, (CH2)r-SO2-(CH2)m, (CH2)r-NR9-(CH2)m, and (CH2)r-O-(CH2)m;
with the further proviso that if G0 is CH, then:
each of R3 and R4 is independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted branched alkyl, substituted or unsubstituted C5-aryl, substituted or unsubstituted C3-C14 heterocycle connected through carbon or nitrogen, and substituted or unsubstituted C5-C14 heteroaryl connected through carbon or nitrogen, or R3 and R4 taken together form a moiety selected from the group consisting of (CHR9)r-(CHR9)m-(CHR9)p, (CHR9)r-S-(CHR9)m, (CHR9)r-SO-(CHR9)m, (CHR9)r-SO2-(CHR9)m, (CHR9)r-NR9-(CHR9)m, and (CHR9)r-O-(CHR9)m;
each G is independently N or CR6, or C when bonded to X, provided that not more than two groups G can be N, and each R6 is independent of each other group R6;
R5 is methyl;
each of R6, R7, R8 is independently selected from the group consisting of H, substituted or unsubstituted alkenyl, C2-C6 substituted or unsubstituted alkynyl, C1-C6 substituted or unsubstituted hydroxyalkyl or aminoalkyl, C3-C6 substituted or unsubstituted cycloalkyl, substituted or unsubstituted C5-C14 aryl, substituted or unsubstituted C5-C14 heteroaryl connected through carbon or a heteroatom, a halogen, CF3, -OCF3, SO2H, SO2(C1-C6 alkyl), heterocycle, SO2-cycloalkyl, SO2NH(C1-C6 alkyl), SO2N(C1-C6 alkyl)(C1-C6 alkyl), SO2NH(C3-C6 cycloalkyl), SO2NH-heterocycle, SO2NH(C3-C6 branched alkyl), NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)(C1-C6 alkyl), NO2, CN, CONH2, CONH(C1-C6 alkyl), CON(C1-C6 alkyl)(C1-C6 alkyl), CO(C1-C6 alkyl), CO-heterocycle, COOH, COO(C1-C6 alkyl), NHCO-(C1-C6 alkyl), and NHCONH-aryl, or any 'of R6 and R7 taken together, or R7 and R8 taken together, or R6 and R8 taken together form a moiety independently selected from the group consisting of -HN-CH=CH-, -HN-N=CH-, -HN-N=N-, -O(CH2)n O-, -S(CH2)n S-, -N=CH-S-, -CH=N-O-, -CH=N-S-, -N=CH-O-, -C=N-O-,-CH=CH-CH=CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -O-CH=CH, and -S-CH=CH-;
A is selected from the group consisting of O, NH, N-(C1-C6 alkyl), CH2, S, SO, and SO2;
G1 is selected from the group consisting of CH and N;
G2 is selected from the group consisting of CR7 and N, with each group R7 being independent of every other group R7;
wherein the substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycle, for each occurence if any, have one or more substituents selected from the group consisting of hydroxy, alkoxy, mercapto, cycloalkyl, heterocyclic, aryl, halogen, cyano, nitro, amino, amido, aldehyde, acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, and sulfuryl;
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers of the compound (A).
2. A compound comprising a first moiety chemically connected to a second moiety, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, wherein the first moiety is selected from the group consisting of:
and wherein the second. moiety is selected from the group consisting of:
and wherein the second. moiety is selected from the group consisting of:
3. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, wherein the compound is of the formula selected from the group consisting of:
4. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
5. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
6. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
7. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
8. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, wherein the compound is selected from the group consisting of:
and
and
9. The compound of claim I, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
10. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
11. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
12. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
13. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
14. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
15. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
16. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
17. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
18. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
19. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
20. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
21. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
22. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
23. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
24. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
25. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
26. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
and
and
27. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
28. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
29. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
30. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
31. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
32 The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
33. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
34. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
35. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
, and
, and
36. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
37. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
38. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
, and
, and
39. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
40. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
41. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is selected from the group consisting of:
, and
, and
42. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
43. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
44. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
45. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
46. The compound of claim 1, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, and N-oxides thereof, wherein the compound is
47. A compound, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, wherein the compound is of the formula selected from the group consisting of:
, and
, and
48. The compound of claim 1, wherein G0 is N.
49. The compound of claim 48, wherein X is a bond, Y is a bond, each p, q and n is 0, and R3 and R4 are taken together with G0 form a heterocyclic ring.
50. The compound of claim 49, wherein each G1 and G2 is CH and R7 is SO2NH-(C3-C6 branched alkyl).
51. The compound of claim 1, wherein X is O.
52. The compound of claim 51, wherein G0 is N.
53. The compound of claim 52, wherein Y is a bond, and each RI and R2 is H.
54. The compound of claim 52 or 53, wherein R3 and R4 taken together with G0 to form a heterocyclic ring.
55. The compound of claim 54, wherein each G1 and G2 is CH and R7 is SO2NH-(C3-C6 branched alkyl).
56. The compound of claim 52 or 53, wherein each R3 and R4 is H.
57. A pharmaceutical composition comprising at least one compound of any one of claims 1-56, or its N-oxides, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, and a pharmaceutically acceptable carrier.
58. A pharmaceutical composition comprising:
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.
59. A pharmaceutical composition comprising:
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.
or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable carrier.
60. A process for making a pharmaceutical composition comprising combining a combination of at least one compound of any one of claims 1-56, or its N-oxide(s), or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual diastereomers thereof, and a pharmaceutically acceptable carrier.
61. A compound, or a salt thereof, wherein the compound is of the formula selected from the group consisting of:
62. The compound of claim 61, or a salt thereof, wherein the compound is of the formula:
63. The compound of claim 61, or a salt thereof, wherein the compound is of the formula:
64. A method for making a compound of the formula XLV:
comprising reacting 3-bromo-N-tert-butyl-benzenesulfonamide with a compound of the formula 32:
comprising reacting 3-bromo-N-tert-butyl-benzenesulfonamide with a compound of the formula 32:
65. The method of claim 64, further comprising purifying a crude product from the step of reacting the compound of the formula 32 with 3-bromo-N-tert-butyl-benzenesulfonamide.
66. A method for making a compound of the formula LVII:
comprising reacting 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine with a compound of the formula 33:
comprising reacting 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine with a compound of the formula 33:
67 The method of claim 66, further comprising purifying a crude product from the step of reacting the compound of the formula 33 with 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine.
68. A pharmaceutical composition for treating a disorder associated with a Janus kinase 2 (JAK2) family kinase comprising a therapeutically effective amount of the compound of any one of claims 1-56, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
69. The pharmaceutical composition of claim 68, wherein said disorder is an angiogenic-associated disorder.
70. The pharmaceutical composition of claim 68, wherein said disorder is a myeloproliferanve disorder, a cancer, eye disease, inflammation, psoriasis, or a viral infection
71. The pharmaceutical composition of claim 68, wherein said disorder is proliferative diabetic retinopathy.
72. The pharmaceutical composition of claim 68, wherein said disorder is any myeloid-linked disorder.
73. The pharmaceutical composition of claim 68, wherein said disorder is a myeloproliferative disorder.
74. The pharmaceutical composition of claim 73, wherein said myeloproliferative disorder arises due to mutations in a kinase.
75. The pharmaceutical composition of claim 73, wherein said myeloproliferative disorder arises due to gain-of-function of a JAK family kinase pathway.
76. The pharmaceutical composition of claim 73, wherein said myeloproliferative disorder arises as a result of gene or protein fusions due to gain-of-function of a JAK family kinase pathway.
77. The pharmaceutical composition of claim 68, wherein said disorder is polycythemia vera.
78. The pharmaceutical composition of claim 68, wherein said disorder is essential thrombocythemia.
79. The pharmaceutical composition of claim 68, wherein said disorder is myeloid fibrosis with myeloid metaplasia.
80. The pharmaceutical composition of claim 68, wherein said disorder is a cancer selected from the group consisting of an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer and brain cancer.
81. The pharmaceutical composition of claim 68, wherein said disorder is leukemia.
82. The pharmaceutical composition of claim 81, wherein said leukemia is acute myelogenous leukemia.
83. The pharmaceutical composition of claim 81, wherein said leukemia is chronic myelogenous leukemia (CML).
84. The pharmaceutical composition of claim 83, wherein said chronic myelogenous leukemia is resistant to current treatments.
85. The pharmaceutical composition of claim 68, wherein the disorder is selected from the group consisting of ocular neovascularization, infantile haemangiomas, organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes, Type II diabetes, complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, blood disorders, asthma, rhinitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, conditions associated with cytokines, glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, allergic asthma, atopic dermatitis, allergic rhinitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft vs. host disease, motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative disease caused by traumatic injury, stroke, glutamate neurotoxicity, hypoxia, ischemic/reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, platelet aggregation, allergic contact dermatitis, hypersensitivity pneumonitis, systemic lupus erythematosus, juvenile arthritis, Sjogren's Syndrome, polymyositis, ankylosing spondylitis, psoriatic arthritis, Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, Human T-lymphotropic virus-1, Varicella-Zoster Virus, Human Papilloma Virus, food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.
86. The pharmaceutical composition of claim 68, wherein the disorder is a cardiovascular disease.
87. The pharmaceutical composition of claim 68, wherein the disorder is a hematological disorder.
88. A pharmaceutical composition for treating a myeloproliferative disorder in a patient comprising a therapeutically effective amount of the compound of claim 4, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
89. A pharmaceutical composition for treating a myeloproliferative disorder in a patient comprising a therapeutically effective amount of the compound of claim 5, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
90. An article of manufacture comprising packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material comprises a label which indicates that the pharmaceutical composition is for use in treatment of a disorder associated with a JAK2 family kinase, and wherein the pharmaceutical composition comprises at least one compound of any one of claims 1-56, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof.
91. The article of manufacture of claim 90, wherein the label indicates that the pharmaceutical composition is for use in treatment of a myeloproliferative disorder, a cancer, eye disease, inflammation, psoriasis, or a viral infection.
92. The article of manufacture of claim 90, wherein the label indicates that the pharmaceutical composition is for use in treatment of any myeloid-linked disorder.
93. The article of manufacture of claim 90, wherein the label indicates that the pharmaceutical composition is for use in treatment of a myeloproliferative disorder.
94. The article of manufacture of claim 90, wherein the label indicates that the pharmaceutical composition is for use in treatment of polycythemia vera.
95. The article of manufacture of claim 90, wherein the label indicates that the pharmaceutical composition is for use in treatment of essential thrombocythemia.
96. The article of manufacture of claim 90, wherein the label indicates that the pharmaceutical composition is for use in treatment of a cancer selected from the group consisting of an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer and brain cancer.
97. The article of manufacture of claim 90, wherein the label indicates that the pharmaceutical composition is for use in treatment of leukemia
98. The article of manufacture of claim 90, wherein the label indicates that the pharmaceutical composition is for use in treatment of a disorder selected from the group consisting of ocular neovascularization, infantile haemangiomas, organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes, Type II diabetes, complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, blood disorders, asthma, rhinitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, conditions associated with cytokines, glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, allergic asthma, atopic dermatitis, allergic rhinitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft vs. host disease, motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative disease caused by traumatic injury, stroke, glutamate neurotoxicity, hypoxia, ischemic/reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, platelet aggregation, allergic contact dermatitis, hypersensitivity pneumonius, systemic lupus erythematosus, juvenile arthritis, Sjogren's Syndrome, polymyositis, ankylosing spondylitis, psoriatic arthritis, Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, Human T-lymphotropic virus-1, Varicella-Zoster Virus, Human Papilloma Virus, food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.
99. A pharmaceutical composition for treating a disorder associated with a JAK2 family kinase in a subject in need of such treatment, comprising a therapeutically effective amount of at least one compound of any one of claims 1-56, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in combination with an anti-inflammatory agent, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody, or a protein kinase inhibitor.
100. A pharmaceutical composition for treating a disorder associated with a family kinase in a subject in need of such treatment, comprising a therapeutically effective amount of at least one compound of any one of claims 1-56, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, and a pharmaceutically acceptable carrier, wherein the composition is used for topical administration.
101. The pharmaceutical composition of claim 100, wherein the composition is used for administration in combination with administration of an anti-inflammatory agent, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody, or a protein kinase inhibitor.
102. The pharmaceutical composition of any one of claims 100 and 101, wherein the disorder is an eye disease.
103. The pharmaceutical composition of claim 102, wherein the pharmaceutical composition is formulated as eye drops.
104. Use of a compound of any one of claims 1-56, or pharmaceutically acceptable salts, hydrates, solvates", crystal forms, N-oxides, and individual diastereomers thereof, for the treatment of a disorder associated with a JAK2 family kinase.
105. The use of claim 104, wherein the disorder is a myeloproliferative disorder.
106. The use according to claim 104, wherein the disorder is polycythemia vera.
107. The use according to claim 104, wherein the disorder is essential thrombocythemia.
108. The use according to claim 104,wherein said disorder is a cancer selected from the group consisting of an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer and brain cancer.
109. The use according to claim 104, wherein the disorder is selected from the group consisting of ocular neovascularization, infantile haemangiomas, organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes, Type II diabetes, complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, blood disorders, asthma, rhinitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, conditions associated with cytokines, glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, allergic asthma, atopic dermatitis, allergic rhinitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft vs. host disease, motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative disease caused by traumatic injury, stroke, glutamate neurotoxicity, hypoxia, ischemic/reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, platelet aggregation, allergic contact dermatitis, hypersensitivity pneumonitis, systemic lupus erythematosus, juvenile arthritis, Sjogren's Syndrome, polymyositis, ankylosing spondylitis, psoriatic arthritis, Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, Human T-lymphotropic virus-1 Varicella-Zoster Virus, Human Papilloma Virus, food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.
110. Use of a compound of any one of claims 1-56, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, in the manufacture of a medicament for the treatment of a disorder associated with a JAK2 family kinase.
111. The use of claim 110, wherein the disorder is a myeloproliferative disorder.
112. The use according to claim 110, wherein the disorder is polycythemia vera.
113. The use according to claim 110, wherein the disorder is essential thrombocythemia.
114. The use according to claim 110,wherein said disorder is a cancer selected from the group consisting of an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer and brain cancer.
115. The use according to claim 110, wherein the disorder is selected from the group consisting of ocular neovascularization, infantile haemangiomas, organ hypoxia, vascular hyperplasia, organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes, Type II diabetes, complications from diabetes, inflammatory disease, acute pancreatitis, chronic pancreatitis, asthma, allergies, adult respiratory distress syndrome, cardiovascular disease, liver disease, blood disorders, asthma, rhinitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, conditions associated with cytokines, glomerulonephritis, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, allergic asthma, atopic dermatitis, allergic rhinitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, graft vs. host disease, motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, neurodegenerative disease caused by traumatic injury, stroke, glutamate neurotoxicity, hypoxia, ischemic/reperfusion injury in stroke, myocardial ischemia, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, platelet aggregation, allergic contact dermatitis, hypersensitivity pneumonitis, systemic lupus erythematosus, juvenile arthritis, Sjogren's Syndrome, polymyositis, ankylosing spondylitis, psoriatic arthritis, Epstein Barr Virus, Hepatitis B, Hepatitis C, HIV, Human T-lymphotropic virus-1, Varicella-Zoster Virus, Human Papilloma Virus, food allergy, cutaneous inflammation, and immune suppression induced by solid tumors.
116. Use of the compound of claim 4, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, for the treatment of a disorder associated with a JAK2 family kinase in a patient.
117. The use of claim 116, wherein the disorder is a myeloproliferative disorder
118. The use according to claim 116, wherein the disorder is polycythemia vera.
119. The use according to claim 116, wherein the disorder is essential thrombocythemia.
120. Use of the compound of claim 4, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, in the manufacture of a medicament for the treatment of a disorder associated with a JAK2 family kinase in a patient
121. The use of claim 120, wherein the disorder is a myeloproliferative disorder.
122. The use according to claim 120, wherein the disorder is polycythemia vera.
123. The use according to claim 120, wherein the disorder is essential thrombocythemia.
124. Use of the compound of claim 5, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, for the treatment of a disorder associated with a JAK2 family kinase in a patient.
125. The use of claim 124, wherein the disorder is a myeloproliferative disorder.
126. The use according to claim 124, wherein the disorder is polycythemia vera.
127. The use according to claim 124, wherein the disorder is essential thrombocythemia
128. Use of the compound of claim 5, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms, N-oxides, and individual diastereomers thereof, in the manufacture of a medicament for the treatment of a disorder associated with a JAK2 family kinase in a patient.
129. The use of claim 128, wherein the disorder is a myeloproliferative disorder.
130. The use according to claim 128, wherein the disorder is polycythemia vera.
131. The use according to claim 128, wherein the disorder is essential thrombocythemia.
132. Use of at least one compound of any one of claims 1-56, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in combination with an anti-inflammatory agent, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody, or a protein kinase inhibitor for the treatment of a disorder associated with a JAK2 family kinase in a subject in need of such treatment.
133. Use of at least one compound of any one of claims 1-56, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in combination with an anti-inflammatory agent, chemotherapeutic agent, immunomodulatory agent, therapeutic antibody, or a protein kinase inhibitor in the manufacture of a medicament for the treatment of a disorder associated with a JAK2 family kinase in a subject in need of such treatment.
134. Use of at least one compound of any one of claims 1-56, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, for the treatment of a disorder associated with a JAK2 family kinase in a subject in need of such treatment, wherein the compound is formulated for topical administration.
135. Use of at least one compound of any one of claims 1-56, or N-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in the manufacture of a medicament for the treatment of a disorder associated with a JAK2 family kinase in a subject in need of such treatment, wherein the compound is formulated for topical administration.
136. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
137. A pharmaceutical composition comprising the compound of claim 136 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or exipient.
138. A pharmaceutical composition for treating a myoproliferative disorder in a patient comprising a therapeutically effective amount of the compound of claim 136, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluents or exipient.
139. Use of a therapeutically effective amount of the compound of claim 136, or a pharmaceutically acceptable salt thereof, for the treatment of a disorder associated with a JAK2 family kinase in a patient in need thereof.
140. Use of the compound of claim 136, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disorder associated with a JAK2 family kinase.
141. The use according to claim 139 or 140, wherein the disorder is a myeloproliferative disorder.
142. The use according to claim 139 or 140, wherein the disorder is polycythemia vera.
143. The use according to claim 139 or 140, wherein the disorder is essential thrombocythemia.
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Families Citing this family (301)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI329105B (en) * | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| ATE451104T1 (en) | 2002-07-29 | 2009-12-15 | Rigel Pharmaceuticals Inc | METHOD FOR TREATING OR PREVENTING AUTOIMMUNE DISEASES USING 2,4-PYRIMIDINEDIAMINE COMPOUNDS |
| US20050282814A1 (en) * | 2002-10-03 | 2005-12-22 | Targegen, Inc. | Vasculostatic agents and methods of use thereof |
| KR20050056227A (en) * | 2002-10-03 | 2005-06-14 | 탈자진 인코포레이티드 | Vasculostatic agents and methods of use thereof |
| WO2005016893A2 (en) | 2003-07-30 | 2005-02-24 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases |
| KR20070011458A (en) | 2004-04-08 | 2007-01-24 | 탈자진 인코포레이티드 | Benzotriazine inhibitors of kinases |
| MX2007002208A (en) * | 2004-08-25 | 2007-05-08 | Targegen Inc | Heterocyclic compounds and methods of use. |
| MX2007008848A (en) * | 2005-06-08 | 2008-04-16 | Targegen Inc | Methods and compositions for the treatment of ocular disorders. |
| US20070203161A1 (en) * | 2006-02-24 | 2007-08-30 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| WO2006133426A2 (en) | 2005-06-08 | 2006-12-14 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| US8133900B2 (en) * | 2005-11-01 | 2012-03-13 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
| RU2597364C2 (en) | 2005-11-01 | 2016-09-10 | Таргеджен, Инк. | Bi-aryl-meta-pyrimidine kinase inhibitors |
| US8604042B2 (en) * | 2005-11-01 | 2013-12-10 | Targegen, Inc. | Bi-aryl meta-pyrimidine inhibitors of kinases |
| US20070149508A1 (en) * | 2005-11-02 | 2007-06-28 | Targegen, Inc. | Six membered heteroaromatic inhibitors targeting resistant kinase mutations |
| WO2007070514A1 (en) * | 2005-12-13 | 2007-06-21 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors |
| CA2642229C (en) | 2006-02-24 | 2015-05-12 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| US7691858B2 (en) * | 2006-04-25 | 2010-04-06 | Targegen, Inc. | Kinase inhibitors and methods of use thereof |
| WO2008008234A1 (en) * | 2006-07-07 | 2008-01-17 | Targegen, Inc. | 2-amino-5-substituted pyrimidine inhibitors |
| US8148391B2 (en) | 2006-10-23 | 2012-04-03 | Cephalon, Inc. | Fused bicyclic derivatives of 2,4-diaminopyrimidine as ALK and c-Met inhibitors |
| EP2097376A2 (en) | 2006-12-22 | 2009-09-09 | F. Hoffmann-Roche AG | Spiro-piperidine derivatives |
| TW200840581A (en) * | 2007-02-28 | 2008-10-16 | Astrazeneca Ab | Novel pyrimidine derivatives |
| US20080214558A1 (en) * | 2007-03-01 | 2008-09-04 | Supergen, Inc. | Pyrimidine-2,4-diamine derivatives and their use as jak2 kinase inhibitors |
| WO2008118822A1 (en) * | 2007-03-23 | 2008-10-02 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| RS58449B1 (en) | 2007-06-13 | 2019-04-30 | Incyte Holdings Corp | Use of salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h- pyrazol-1-yl)-3- cyclopentylpropanenitrile |
| MX2010000658A (en) * | 2007-07-16 | 2010-03-26 | Astrazeneca Ab | Pyrimidine derivatives 934. |
| US8993585B2 (en) | 2007-07-17 | 2015-03-31 | Rigel Pharmaceuticals, Inc. | Cyclic amine substituted pyrimidinediamines as PKC inhibitors |
| AU2008296545B2 (en) | 2007-08-28 | 2011-09-29 | Irm Llc | 2 -biphenylamino-4 -aminopyrimidine derivatives as kinase inhibitors |
| CA2960659C (en) * | 2007-11-09 | 2021-07-13 | The Salk Institute For Biological Studies | Use of tam receptor inhibitors as immunoenhancers and tam activators as immunosuppressors |
| US20100310563A1 (en) * | 2007-11-30 | 2010-12-09 | Bumm Thomas G P | Methods for treating induced cellular proliferative disorders |
| KR101244517B1 (en) | 2008-01-11 | 2013-03-18 | 에프. 호프만-라 로슈 아게 | Modulators for amyloid beta |
| JP5328816B2 (en) * | 2008-02-22 | 2013-10-30 | エフ．ホフマン−ラ ロシュ アーゲー | Modulator of amyloid β |
| WO2009105675A1 (en) * | 2008-02-22 | 2009-08-27 | Rigel Pharmaceuticals, Inc. | Use of 2,4-pyrimidinediamines for the treatment of atherosclerosis |
| CA2723358A1 (en) * | 2008-05-05 | 2009-11-12 | Allison B. Reiss | Method for improving cardiovascular risk profile of cox inhibitors |
| EA029131B1 (en) | 2008-05-21 | 2018-02-28 | Ариад Фармасьютикалз, Инк. | Phosphorous derivatives as kinase inhibitors |
| US9273077B2 (en) | 2008-05-21 | 2016-03-01 | Ariad Pharmaceuticals, Inc. | Phosphorus derivatives as kinase inhibitors |
| UY31929A (en) | 2008-06-25 | 2010-01-05 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS CINASE INHIBITORS |
| JP2011526299A (en) | 2008-06-27 | 2011-10-06 | アビラ セラピューティクス， インコーポレイテッド | Heteroaryl compounds and their use |
| US11351168B1 (en) | 2008-06-27 | 2022-06-07 | Celgene Car Llc | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
| US8338439B2 (en) * | 2008-06-27 | 2012-12-25 | Celgene Avilomics Research, Inc. | 2,4-disubstituted pyrimidines useful as kinase inhibitors |
| WO2010011349A2 (en) * | 2008-07-25 | 2010-01-28 | Supergen, Inc. | Pyrimidine-2,4-diamine jak2 kinase inhibiting anti-inflammation use |
| RU2011108563A (en) * | 2008-08-05 | 2012-09-10 | Таргеджен, Инк. (US) | THALASSEMIA TREATMENT METHODS |
| CL2009001884A1 (en) * | 2008-10-02 | 2010-05-14 | Incyte Holdings Corp | Use of 3-cyclopentyl-3- [4- (7h-pyrrolo [2,3-d] pyrimidin-4-yl) -1h-pyrazol-1-yl) propanonitrile, janus kinase inhibitor, and use of a composition that understands it for the treatment of dry eye. |
| WO2010040661A1 (en) | 2008-10-09 | 2010-04-15 | F. Hoffmann-La Roche Ag | Modulators for amyloid beta |
| JP5378532B2 (en) | 2008-11-10 | 2013-12-25 | エフ．ホフマン−ラ ロシュ アーゲー | Heterocyclic γ-secretase modulator |
| US20110245156A1 (en) * | 2008-12-09 | 2011-10-06 | Cytokine Pharmasciences, Inc. | Novel antiviral compounds, compositions, and methods of use |
| WO2010093808A1 (en) | 2009-02-11 | 2010-08-19 | Reaction Biology Corp. | Selective kinase inhibitors |
| WO2010112210A1 (en) * | 2009-04-03 | 2010-10-07 | Cellzome Ag | Methods for the identification of kinase interacting molecules and for the purification of kinase proteins |
| CA2758614A1 (en) * | 2009-04-14 | 2010-10-21 | Cellzome Limited | Fluoro substituted pyrimidine compounds as jak3 inhibitors |
| US9908884B2 (en) | 2009-05-05 | 2018-03-06 | Dana-Farber Cancer Institute, Inc. | EGFR inhibitors and methods of treating disorders |
| TW201040162A (en) * | 2009-05-06 | 2010-11-16 | Portola Pharm Inc | Inhibitors of JAK |
| AU2010249380B2 (en) | 2009-05-22 | 2015-08-20 | Incyte Holdings Corporation | N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as Janus kinase inhibitors |
| EP3643312A1 (en) | 2009-05-22 | 2020-04-29 | Incyte Holdings Corporation | 3-[4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h-pyrazol-1-yl]octane- or heptane-nitrile as jak inhibitors |
| PL2448938T3 (en) | 2009-06-29 | 2014-11-28 | Incyte Holdings Corp | Pyrimidinones as pi3k inhibitors |
| JP2012197231A (en) * | 2009-08-06 | 2012-10-18 | Oncotherapy Science Ltd | Pyridine and pyrimidine derivative having ttk-inhibiting action |
| AR078012A1 (en) | 2009-09-01 | 2011-10-05 | Incyte Corp | HETEROCICLIC DERIVATIVES OF PIRAZOL-4-IL-PIRROLO (2,3-D) PYRIMIDINS AS INHIBITORS OF THE QUANASA JANUS |
| JP5699149B2 (en) * | 2009-09-04 | 2015-04-08 | バイオジェン・アイデック・エムエイ・インコーポレイテッド | Bruton type tyrosine kinase inhibitor |
| WO2011029807A1 (en) * | 2009-09-11 | 2011-03-17 | Cellzome Limited | Ortho substituted pyrimidine compounds as jak inhibitors |
| NZ620174A (en) | 2009-09-16 | 2016-08-26 | Celgene Avilomics Res Inc | Protein kinase conjugates and inhibitors |
| AP2012006192A0 (en) | 2009-10-15 | 2012-04-30 | Pfizer | PyrroloÄ2,3-DÜ pyrimidine compounds. |
| EA021439B1 (en) * | 2009-11-03 | 2015-06-30 | ГЛЭКСОСМИТКЛАЙН ЭлЭлСи | Quinazoline compounds |
| WO2011056739A1 (en) * | 2009-11-03 | 2011-05-12 | Glaxosmithkline Llc | Compounds and methods |
| EP2513111B1 (en) * | 2009-12-14 | 2013-10-02 | Merck Sharp & Dohme B.V. | Mk2 inhibitors |
| WO2011075643A1 (en) | 2009-12-18 | 2011-06-23 | Incyte Corporation | Substituted heteroaryl fused derivatives as pi3k inhibitors |
| ES2461967T3 (en) | 2009-12-18 | 2014-05-21 | Pfizer Inc. | Pyrrolo [2,3-d] pyrimidine compounds |
| AU2010334804B2 (en) * | 2009-12-23 | 2015-04-02 | Palau Pharma, S.L.U. | Aminoalkylpyrimidine derivatives as histamine H4 receptor antagonists |
| AU2010339456A1 (en) | 2009-12-30 | 2012-07-05 | Celgene Avilomics Research, Inc. | Ligand-directed covalent modification of protein |
| JP2013517273A (en) * | 2010-01-13 | 2013-05-16 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | Compounds and methods |
| US8486967B2 (en) | 2010-02-17 | 2013-07-16 | Hoffmann-La Roche Inc. | Heteroaryl substituted piperidines |
| CN102985417B (en) * | 2010-03-10 | 2015-01-28 | 因塞特公司 | Piperidin-4-yl azetidine derivatives as JAK1 inhibitors |
| AU2011234644B2 (en) | 2010-03-30 | 2014-07-17 | Novartis Ag | PKC inhibitors for the treatment of B-cell lymphoma having chronic active B-cell-receptor signalling |
| US9193721B2 (en) | 2010-04-14 | 2015-11-24 | Incyte Holdings Corporation | Fused derivatives as PI3Kδ inhibitors |
| AU2011252799B2 (en) | 2010-05-14 | 2015-05-14 | Cold Spring Harbor Laboratory | Compositions and methods for treating leukemia |
| EP2571875A4 (en) | 2010-05-14 | 2013-10-30 | Dana Farber Cancer Inst Inc | Male contraceptive compositions and methods of use |
| ES2534521T3 (en) | 2010-05-14 | 2015-04-23 | Dana-Farber Cancer Institute, Inc. | Compositions and their use in the treatment of neoplasia, inflammatory diseases and other diseases |
| CA2798578C (en) | 2010-05-21 | 2015-12-29 | Chemilia Ab | Novel pyrimidine derivatives |
| EA035981B1 (en) | 2010-05-21 | 2020-09-09 | Инсайт Холдингс Корпорейшн | Jak inhibitor formulation for topical application |
| WO2011149827A1 (en) * | 2010-05-24 | 2011-12-01 | Glaxosmithkline Llc | Compounds and methods |
| EP2603081B1 (en) | 2010-08-10 | 2016-10-05 | Celgene Avilomics Research, Inc. | Besylate salt of a btk inhibitor |
| RU2644151C2 (en) | 2010-11-01 | 2018-02-08 | Селджен Авиломикс Рисерч, Инк. | Heterocyclic compounds and their application |
| JP5956999B2 (en) | 2010-11-01 | 2016-07-27 | セルジーン アヴィロミクス リサーチ， インコーポレイテッド | Heteroaryl compounds and uses thereof |
| WO2012060847A1 (en) | 2010-11-07 | 2012-05-10 | Targegen, Inc. | Compositions and methods for treating myelofibrosis |
| EP2637502B1 (en) | 2010-11-10 | 2018-01-10 | Celgene CAR LLC | Mutant-selective egfr inhibitors and uses thereof |
| TW201249845A (en) | 2010-11-19 | 2012-12-16 | Incyte Corp | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
| EP2640725B1 (en) | 2010-11-19 | 2015-01-07 | Incyte Corporation | Heterocyclic-substituted pyrrolopyridines and pyrrolopyrimidines as jak inhibitors |
| TW201249844A (en) | 2010-12-20 | 2012-12-16 | Incyte Corp | N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors |
| WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
| US9108984B2 (en) * | 2011-03-14 | 2015-08-18 | Incyte Corporation | Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors |
| EP2688883B1 (en) | 2011-03-24 | 2016-05-18 | Noviga Research AB | Pyrimidine derivatives |
| WO2012135009A1 (en) * | 2011-03-25 | 2012-10-04 | Incyte Corporation | Pyrimidine-4,6-diamine derivatives as pi3k inhibitors |
| US9249124B2 (en) | 2011-03-30 | 2016-02-02 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Aurora kinase inhibitors and methods of making and using thereof |
| US8703767B2 (en) | 2011-04-01 | 2014-04-22 | University Of Utah Research Foundation | Substituted N-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase BTK inhibitors |
| JP6118794B2 (en) * | 2011-04-01 | 2017-04-19 | ザ ユニバーシティ オブ ユタ リサーチ ファウンデイション | Substituted N-phenylpyrimidin-2-amine analogs as inhibitors of AXL kinase |
| WO2012151561A1 (en) | 2011-05-04 | 2012-11-08 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| WO2012177606A1 (en) | 2011-06-20 | 2012-12-27 | Incyte Corporation | Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors |
| TW201313721A (en) | 2011-08-18 | 2013-04-01 | Incyte Corp | Cyclohexyl azetidine derivatives as JAK inhibitors |
| KR101982475B1 (en) | 2011-09-02 | 2019-05-27 | 인사이트 홀딩스 코포레이션 | Heterocyclylamines as pi3k inhibitors |
| UA111854C2 (en) | 2011-09-07 | 2016-06-24 | Інсайт Холдінгс Корпорейшн | METHODS AND INTERMEDIATE COMPOUNDS FOR JAK INHIBITORS |
| WO2013059548A1 (en) | 2011-10-19 | 2013-04-25 | Sanofi | Compositions and methods for treating cancer using jak2 inhibitor |
| WO2013063401A1 (en) | 2011-10-28 | 2013-05-02 | Celgene Avilomics Research, Inc. | Methods of treating a bruton's tyrosine kinase disease or disorder |
| CN102429901B (en) * | 2011-11-03 | 2013-11-06 | 合肥博太医药生物技术发展有限公司 | Application of indole-3-carbinol, diindolylmethane and derivatives thereof in preparation of medicaments for preventing and treating renal fibrosis |
| ES2698298T3 (en) | 2012-03-15 | 2019-02-04 | Celgene Car Llc | Salts of an epidermal growth factor receptor kinase inhibitor |
| CN104302178B (en) | 2012-03-15 | 2018-07-13 | 西建卡尔有限责任公司 | The solid form of epidermal growth factor receptor kinase inhibitor |
| AR090548A1 (en) | 2012-04-02 | 2014-11-19 | Incyte Corp | BICYCLIC AZAHETEROCICLOBENCILAMINS AS PI3K INHIBITORS |
| WO2013169401A1 (en) | 2012-05-05 | 2013-11-14 | Ariad Pharmaceuticals, Inc. | Compounds for inhibiting cell proliferation in egfr-driven cancers |
| TW201406761A (en) | 2012-05-18 | 2014-02-16 | Incyte Corp | Piperidinylcyclobutyl substituted pyrrolopyridine and pyrrolopyrimidine derivatives as JAK inhibitors |
| US9353087B2 (en) | 2012-06-08 | 2016-05-31 | Biogen Ma Inc. | Inhibitors of Bruton's tyrosine kinase |
| AR091273A1 (en) | 2012-06-08 | 2015-01-21 | Biogen Idec Inc | PYRIMIDINYL TIROSINE KINASE INHIBITORS |
| BR112014030812B1 (en) | 2012-06-13 | 2022-11-08 | Incyte Holdings Corporation | SUBSTITUTED TRICYCLIC COMPOUNDS AS FGFR INHIBITORS, THEIR USES, PHARMACEUTICAL COMPOSITION AND METHOD FOR INHIBITING A FGFR ENZYME |
| KR102427777B1 (en) | 2012-06-26 | 2022-08-01 | 델 마 파마슈티컬스 | Methods for treating tyrosine-kinase-inhibitor-resistant malignancies in patients with genetic polymorphisms or ahi1 dysregulations or mutations employing dianhydrogalactitol, diacetyldianhydrogalactitol, dibromodulcitol, or analogs or derivatives thereof |
| US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
| US9296703B2 (en) | 2012-10-04 | 2016-03-29 | University Of Utah Research Foundation | Substituted N-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase BTK inhibitors |
| EP2903972B1 (en) | 2012-10-04 | 2019-12-04 | University of Utah Research Foundation | Substituted n-(3-(pyrimidin-4-yl)phenyl)acrylamide analogs as tyrosine receptor kinase btk inhibitors |
| CN113384545A (en) | 2012-11-15 | 2021-09-14 | 因赛特公司 | Sustained release dosage forms of ruxolitinib |
| US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
| EP2935226A4 (en) | 2012-12-21 | 2016-11-02 | Celgene Avilomics Res Inc | Heteroaryl compounds and uses thereof |
| KR20150119012A (en) | 2013-02-08 | 2015-10-23 | 셀진 아빌로믹스 리서치, 인코포레이티드 | Erk inhibitors and uses thereof |
| SI3489239T1 (en) | 2013-03-06 | 2022-04-29 | Incyte Holdings Corporation | Processes and intermediates for making a jak inhibitor |
| WO2014159392A1 (en) | 2013-03-14 | 2014-10-02 | Dana-Farber Cancer Institute, Inc. | Bromodomain binding reagents and uses thereof |
| ES2738493T3 (en) | 2013-03-14 | 2020-01-23 | Tolero Pharmaceuticals Inc | JAK2 and ALK2 inhibitors and methods for their use |
| WO2014151761A1 (en) | 2013-03-15 | 2014-09-25 | Ariad Pharmaceuticals, Inc. | Novel choline kinase inhibitors |
| US9611283B1 (en) | 2013-04-10 | 2017-04-04 | Ariad Pharmaceuticals, Inc. | Methods for inhibiting cell proliferation in ALK-driven cancers |
| US9210831B2 (en) | 2013-04-15 | 2015-12-08 | International Business Machines Corporation | Separable and integrated heat sinks facilitating cooling multi-compnent electronic assembly |
| SG10201708520YA (en) | 2013-04-19 | 2017-12-28 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors |
| PL3004079T3 (en) * | 2013-06-04 | 2018-07-31 | Acturum Real Estate Ab | Pyrimidine compounds and their use as gamma secretase modulators |
| KR20160034379A (en) | 2013-07-25 | 2016-03-29 | 다나-파버 캔서 인스티튜트 인크. | Inhibitors of transcription factors and uses thereof |
| EP3030241A4 (en) * | 2013-08-06 | 2019-06-19 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Inhibitors of ack1/tnk2 tyrosine kinase |
| EA201690357A1 (en) | 2013-08-07 | 2016-07-29 | Инсайт Корпорейшн | DOSAGE FORMS WITH Slow Release For JAK1 Inhibitor |
| US9492471B2 (en) | 2013-08-27 | 2016-11-15 | Celgene Avilomics Research, Inc. | Methods of treating a disease or disorder associated with Bruton'S Tyrosine Kinase |
| CN105849110B (en) | 2013-11-08 | 2019-08-02 | 达纳-法伯癌症研究所有限公司 | Use the combination treatment for cancer of bromine structural domain and additional terminals (BET) protein inhibitor |
| LT3080103T (en) | 2013-12-11 | 2018-08-10 | Biogen Ma Inc. | Biaryl compounds useful for the treatment of human diseases in oncology, neurology and immunology |
| US9415049B2 (en) | 2013-12-20 | 2016-08-16 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
| CA2936865A1 (en) | 2014-01-31 | 2015-08-06 | Dana-Farber Cancer Institute, Inc. | Diaminopyrimidine benzenesulfone derivatives and uses thereof |
| US10793571B2 (en) | 2014-01-31 | 2020-10-06 | Dana-Farber Cancer Institute, Inc. | Uses of diazepane derivatives |
| BR112016017045A2 (en) | 2014-01-31 | 2017-08-08 | Dana Farber Cancer Inst Inc | DIAZEPANE DERIVATIVES AND USES THEREOF |
| JP6526065B2 (en) | 2014-02-28 | 2019-06-05 | ニンバス ラクシュミ， インコーポレイテッド | TYK2 inhibitors and uses thereof |
| MX2016011160A (en) | 2014-02-28 | 2017-04-27 | Tensha Therapeutics Inc | Treatment of conditions associated with hyperinsulinaemia. |
| US9498467B2 (en) | 2014-05-30 | 2016-11-22 | Incyte Corporation | Treatment of chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML) by inhibitors of JAK1 |
| US10077277B2 (en) | 2014-06-11 | 2018-09-18 | Incyte Corporation | Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors |
| US10106507B2 (en) * | 2014-08-03 | 2018-10-23 | H. Lee Moffitt Cancer Center and Research Insitute, Inc. | Potent dual BRD4-kinase inhibitors as cancer therapeutics |
| WO2016022970A1 (en) | 2014-08-08 | 2016-02-11 | Dana-Farber Cancer Institute, Inc. | Dihydropteridinone derivatives and uses thereof |
| CN106715437A (en) | 2014-08-08 | 2017-05-24 | 达纳-法伯癌症研究所股份有限公司 | Diazepane derivatives and uses thereof |
| AU2015303835B2 (en) | 2014-08-12 | 2020-04-09 | Monash University | Lymph directing prodrugs |
| DK3179858T3 (en) | 2014-08-13 | 2019-07-22 | Celgene Car Llc | Forms and compositions of an ERK inhibitor |
| TWI679205B (en) * | 2014-09-02 | 2019-12-11 | 日商日本新藥股份有限公司 | Pyrazolothiazole compounds and medicine |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| EP3212654B1 (en) | 2014-10-27 | 2020-04-08 | Tensha Therapeutics, Inc. | Bromodomain inhibitors |
| US10480375B2 (en) | 2014-10-28 | 2019-11-19 | Cummins Emission Solutions Inc. | SCR conversion efficiency diagnostics |
| WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
| AU2016219822B2 (en) | 2015-02-20 | 2020-07-09 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
| MA41551A (en) | 2015-02-20 | 2017-12-26 | Incyte Corp | BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS |
| ES2843522T3 (en) | 2015-02-27 | 2021-07-19 | Incyte Corp | PI3K inhibitor salts and processes for their preparation |
| ES2930585T3 (en) | 2015-02-27 | 2022-12-19 | Nimbus Lakshmi Inc | TYK2 inhibitors and uses thereof |
| US9732097B2 (en) | 2015-05-11 | 2017-08-15 | Incyte Corporation | Process for the synthesis of a phosphoinositide 3-kinase inhibitor |
| US9988401B2 (en) | 2015-05-11 | 2018-06-05 | Incyte Corporation | Crystalline forms of a PI3K inhibitor |
| US10702527B2 (en) | 2015-06-12 | 2020-07-07 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
| WO2017004134A1 (en) | 2015-06-29 | 2017-01-05 | Nimbus Iris, Inc. | Irak inhibitors and uses thereof |
| US10494378B2 (en) * | 2015-07-21 | 2019-12-03 | Guangzhou Maxinovel Pharmaceuticals Co., Ltd. | Fused ring pyrimidine compound, intermediate, and preparation method, composition and use thereof |
| JP6802263B2 (en) | 2015-09-02 | 2020-12-16 | ニンバス ラクシュミ， インコーポレイテッド | TYK2 inhibitor and its use |
| US11738087B2 (en) | 2015-09-08 | 2023-08-29 | Monash University | Lymph directing prodrugs |
| JP2018526424A (en) | 2015-09-11 | 2018-09-13 | ダナ−ファーバー キャンサー インスティテュート， インコーポレイテッド | Acetamidhienotriazolodiazepines and their use |
| CN108472300A (en) | 2015-09-11 | 2018-08-31 | 达纳-法伯癌症研究所股份有限公司 | Cyano thiophene and triazol diazacyclo heptantriene and application thereof |
| US10683308B2 (en) | 2015-09-11 | 2020-06-16 | Navitor Pharmaceuticals, Inc. | Rapamycin analogs and uses thereof |
| US10738016B2 (en) | 2015-10-13 | 2020-08-11 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | BRD4-kinase inhibitors as cancer therapeutics |
| PT3364958T (en) | 2015-10-23 | 2023-04-10 | Navitor Pharm Inc | Modulators of sestrin-gator2 interaction and uses thereof |
| WO2017091681A1 (en) | 2015-11-24 | 2017-06-01 | Aclaris Therapeutics, Inc. | Selective kinase inhibitors |
| SG10201913450PA (en) | 2015-11-25 | 2020-03-30 | Dana Farber Cancer Inst Inc | Bivalent bromodomain inhibitors and uses thereof |
| GB201521919D0 (en) | 2015-12-11 | 2016-01-27 | Electrophoretics Ltd | Isobaric mass labels |
| WO2017106352A1 (en) | 2015-12-14 | 2017-06-22 | Raze Therapeutics, Inc. | Caffeine inhibitors of mthfd2 and uses thereof |
| EP3426244B1 (en) | 2016-03-09 | 2023-06-07 | Raze Therapeutics, Inc. | 3-phosphoglycerate dehydrogenase inhibitors and uses thereof |
| RS62271B1 (en) | 2016-03-09 | 2021-09-30 | Raze Therapeutics Inc | 3-phosphoglycerate dehydrogenase inhibitors and uses thereof |
| CA3019394A1 (en) | 2016-04-08 | 2017-10-12 | X4 Pharmaceuticals, Inc. | Methods for treating cancer |
| CN109153650A (en) * | 2016-04-15 | 2019-01-04 | Epizyme股份有限公司 | The aryl or heteroaryl compound that amine as EHMT1 and EHMT2 inhibitor replaces |
| EP3808748A1 (en) | 2016-06-21 | 2021-04-21 | X4 Pharmaceuticals, Inc. | Substituted piperidines as cxcr4-inhibitors |
| CN109641838A (en) | 2016-06-21 | 2019-04-16 | X4 制药有限公司 | CXCR4 inhibitor and application thereof |
| WO2017223229A1 (en) | 2016-06-21 | 2017-12-28 | X4 Pharmaceuticals, Inc. | Cxcr4 inhibitors and uses thereof |
| RU2019104758A (en) | 2016-07-21 | 2020-08-21 | Байоджен Ма Инк. | SUCCINATE FORMS AND COMPOSITIONS OF BRUTON TYROSINE KINASE INHIBITORS |
| CA3039202A1 (en) | 2016-10-14 | 2018-04-19 | Nimbus Lakshmi, Inc. | Tyk2 inhibitors and uses thereof |
| WO2018075937A1 (en) | 2016-10-21 | 2018-04-26 | Nimbus Lakshmi, Inc. | Tyk2 inhibitors and uses thereof |
| EP3538091A4 (en) | 2016-11-08 | 2020-06-10 | Navitor Pharmaceuticals, Inc. | PHENYL AMINO PIPERIDINE mTORC INHIBITORS AND USES THEREOF |
| AU2017368050A1 (en) | 2016-11-29 | 2019-06-20 | Puretech Lyt, Inc. | Exosomes for delivery of therapeutic agents |
| WO2018106636A1 (en) | 2016-12-05 | 2018-06-14 | Raze Therapeutics, Inc. | Shmt inhibitors and uses thereof |
| US11730819B2 (en) | 2016-12-23 | 2023-08-22 | Bicycletx Limited | Peptide derivatives having novel linkage structures |
| WO2018127699A1 (en) | 2017-01-06 | 2018-07-12 | Bicyclerd Limited | Compounds for treating cancer |
| EP4338802A2 (en) | 2017-03-08 | 2024-03-20 | Takeda Pharmaceutical Company Limited | Tyk2 inhibitors, uses, and methods for production thereof |
| EP3375778A1 (en) | 2017-03-14 | 2018-09-19 | Artax Biopharma Inc. | Aryl-piperidine derivatives |
| EP3375784A1 (en) | 2017-03-14 | 2018-09-19 | Artax Biopharma Inc. | Aza-dihydro-acridone derivatives |
| US10342766B2 (en) * | 2017-03-23 | 2019-07-09 | North Carolina Agricultural And Technical State University | 6-shogaol derivatives and activities thereof |
| WO2018191146A1 (en) | 2017-04-10 | 2018-10-18 | Navitor Pharmaceuticals, Inc. | Heteroaryl rheb inhibitors and uses thereof |
| JP2020517618A (en) | 2017-04-21 | 2020-06-18 | エピザイム，インコーポレイティド | Combination therapy with EHMT2 inhibitor |
| CN110809467B (en) | 2017-04-26 | 2023-03-10 | 纳维托制药有限公司 | Modulators of SESTRIN-GATOR2 interactions and uses thereof |
| US10857196B2 (en) | 2017-04-27 | 2020-12-08 | Bicycletx Limited | Bicyclic peptide ligands and uses thereof |
| AR111960A1 (en) | 2017-05-26 | 2019-09-04 | Incyte Corp | CRYSTALLINE FORMS OF A FGFR INHIBITOR AND PROCESSES FOR ITS PREPARATION |
| US10899798B2 (en) | 2017-06-26 | 2021-01-26 | Bicyclerd Limited | Bicyclic peptide ligands with detectable moieties and uses thereof |
| CN111194317A (en) | 2017-07-28 | 2020-05-22 | 林伯士拉克许米公司 | TYK2 inhibitor and application thereof |
| WO2019034866A1 (en) | 2017-08-14 | 2019-02-21 | Bicyclerd Limited | Bicyclic peptide ligand sting conjugates and uses thereof |
| WO2019034868A1 (en) | 2017-08-14 | 2019-02-21 | Bicyclerd Limited | Bicyclic peptide ligand prr-a conjugates and uses thereof |
| US11883497B2 (en) | 2017-08-29 | 2024-01-30 | Puretech Lyt, Inc. | Lymphatic system-directing lipid prodrugs |
| AU2018324037A1 (en) | 2017-08-29 | 2020-04-16 | Monash University | Lymphatic system-directing lipid prodrugs |
| WO2019060693A1 (en) | 2017-09-22 | 2019-03-28 | Kymera Therapeutics, Inc. | Crbn ligands and uses thereof |
| JP7366031B2 (en) | 2017-09-22 | 2023-10-20 | カイメラ セラピューティクス， インコーポレイテッド | Proteolytic agents and their use |
| CA3079273A1 (en) * | 2017-10-18 | 2019-04-25 | Epizyme, Inc. | Amine-substituted heterocyclic compounds as ehmt2 inhibitors, salts thereof, and methods of synthesis thereof |
| US10596161B2 (en) | 2017-12-08 | 2020-03-24 | Incyte Corporation | Low dose combination therapy for treatment of myeloproliferative neoplasms |
| GB201721265D0 (en) | 2017-12-19 | 2018-01-31 | Bicyclerd Ltd | Bicyclic peptide ligands specific for EphA2 |
| US11304954B2 (en) | 2017-12-19 | 2022-04-19 | Puretech Lyt, Inc. | Lipid prodrugs of mycophenolic acid and uses thereof |
| TWI825046B (en) | 2017-12-19 | 2023-12-11 | 英商拜西可泰克斯有限公司 | Bicyclic peptide ligands specific for epha2 |
| WO2019126378A1 (en) | 2017-12-19 | 2019-06-27 | Ariya Therapeutics, Inc. | Lipid prodrugs of mycophenolic acid and uses thereof |
| US11608345B1 (en) | 2017-12-19 | 2023-03-21 | Puretech Lyt, Inc. | Lipid prodrugs of rapamycin and its analogs and uses thereof |
| BR112020012997A2 (en) | 2017-12-26 | 2020-12-01 | Kymera Therapeutics, Inc. | irak degraders and uses thereof |
| US11485743B2 (en) | 2018-01-12 | 2022-11-01 | Kymera Therapeutics, Inc. | Protein degraders and uses thereof |
| WO2019140387A1 (en) | 2018-01-12 | 2019-07-18 | Kymera Therapeutics, Inc. | Crbn ligands and uses thereof |
| EP3578555B1 (en) * | 2018-01-16 | 2022-09-21 | Shenzhen TargetRx, Inc. | Diphenylaminopyrimidine compound for inhibiting kinase activity |
| CA3089769A1 (en) | 2018-01-29 | 2019-08-01 | Merck Patent Gmbh | Gcn2 inhibitors and uses thereof |
| SG11202006701TA (en) | 2018-01-29 | 2020-08-28 | Merck Patent Gmbh | Gcn2 inhibitors and uses thereof |
| SI3746429T1 (en) | 2018-01-30 | 2023-01-31 | Incyte Corporation | Processes for preparing (1-(3-fluoro-2-(trifluoromethyl)isonicotinyl)piperidine-4-one) |
| EP3746430A4 (en) * | 2018-02-02 | 2021-11-03 | Padforward LLC | Inhibitors of protein arginine deiminases |
| CN112189009B (en) | 2018-02-27 | 2023-09-29 | 阿塔克斯生物制药有限公司 | Chromene derivatives as inhibitors of TCR-NCK interactions |
| WO2019191684A1 (en) | 2018-03-30 | 2019-10-03 | Incyte Corporation | Treatment of hidradenitis suppurativa using jak inhibitors |
| US11013741B1 (en) | 2018-04-05 | 2021-05-25 | Sumitomo Dainippon Pharma Oncology, Inc. | AXL kinase inhibitors and use of the same |
| KR102063155B1 (en) | 2018-04-11 | 2020-01-08 | 한국과학기술연구원 | multi-substituted pyrimidine derivatives showing excellent kinase inhibitory activities |
| WO2019209757A1 (en) | 2018-04-24 | 2019-10-31 | Vertex Pharmaceuticals Incorporated | Pteridinone compounds and uses thereof |
| HUE058746T2 (en) | 2018-04-24 | 2022-09-28 | Merck Patent Gmbh | Antiproliferation compounds and uses thereof |
| KR20210018265A (en) | 2018-05-04 | 2021-02-17 | 인사이트 코포레이션 | Solid form of FGFR inhibitor and method for preparing same |
| SG11202010882XA (en) | 2018-05-04 | 2020-11-27 | Incyte Corp | Salts of an fgfr inhibitor |
| US10980784B2 (en) | 2018-06-15 | 2021-04-20 | Navitor Pharmaceuticals, Inc. | Rapamycin analogs and uses thereof |
| US11180531B2 (en) | 2018-06-22 | 2021-11-23 | Bicycletx Limited | Bicyclic peptide ligands specific for Nectin-4 |
| GB201810316D0 (en) | 2018-06-22 | 2018-08-08 | Bicyclerd Ltd | Peptide ligands for binding to EphA2 |
| WO2020010177A1 (en) | 2018-07-06 | 2020-01-09 | Kymera Therapeutics, Inc. | Tricyclic crbn ligands and uses thereof |
| CA3103995A1 (en) | 2018-07-26 | 2020-01-30 | Sumitomo Dainippon Pharma Oncology, Inc. | Methods for treating diseases associated with abnormal acvr1 expression and acvr1 inhibitors for use in the same |
| US10548889B1 (en) | 2018-08-31 | 2020-02-04 | X4 Pharmaceuticals, Inc. | Compositions of CXCR4 inhibitors and methods of preparation and use |
| EP3846793B1 (en) | 2018-09-07 | 2024-01-24 | PIC Therapeutics, Inc. | Eif4e inhibitors and uses thereof |
| US20220031699A1 (en) | 2018-09-25 | 2022-02-03 | Impact Biomedicines, Inc. | Methods of treating myeloproliferative disorders |
| CA3115088A1 (en) | 2018-10-15 | 2020-04-23 | Nimbus Lakshmi, Inc. | Tyk2 inhibitors and uses thereof |
| JP2022512779A (en) | 2018-10-23 | 2022-02-07 | バイスクルテクス・リミテッド | Bicyclic peptide ligands and their use |
| US11345654B2 (en) | 2018-10-24 | 2022-05-31 | Navitor Pharmaceuticals, Inc. | Polymorphic compounds and uses thereof |
| WO2020092015A1 (en) * | 2018-11-02 | 2020-05-07 | University Of Rochester | Therapeutic mitigation of epithelial infection |
| US11053241B2 (en) | 2018-11-30 | 2021-07-06 | Nimbus Lakshmi, Inc. | TYK2 inhibitors and uses thereof |
| WO2020113233A1 (en) | 2018-11-30 | 2020-06-04 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
| EP3670659A1 (en) | 2018-12-20 | 2020-06-24 | Abivax | Biomarkers, and uses in treatment of viral infections, inflammations, or cancer |
| CA3126034A1 (en) | 2019-01-23 | 2020-07-30 | Nimbus Lakshmi, Inc. | Tyk2 inhibitors and uses thereof |
| FR3092581A1 (en) * | 2019-02-12 | 2020-08-14 | Impact Biomedicines, Inc | CRYSTALLINE FORMS OF A JAK2 INHIBITOR |
| US20230250068A1 (en) * | 2019-02-12 | 2023-08-10 | Inpact Biomedicines, Inc. | Crystalline forms of a jak2 inhibitor |
| WO2020165600A1 (en) | 2019-02-14 | 2020-08-20 | Bicycletx Limited | Bicyclic peptide ligand sting conjugates and uses thereof |
| US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
| EP3946462A1 (en) | 2019-04-02 | 2022-02-09 | BicycleTX Limited | Bicycle toxin conjugates and uses thereof |
| SG11202110829YA (en) | 2019-04-05 | 2021-10-28 | Kymera Therapeutics Inc | Stat degraders and uses thereof |
| CA3141826A1 (en) | 2019-05-31 | 2020-12-03 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
| WO2020256739A1 (en) | 2019-06-21 | 2020-12-24 | Constellation Pharmaceuticals, Inc. | Methods of treating myeloproliferative disorders |
| WO2021091535A1 (en) | 2019-11-05 | 2021-05-14 | Constellation Pharmaceuticals, Inc. | Treating myeloproliferative disorders with cpi-0610 and a jak inhibitor |
| WO2020257644A1 (en) | 2019-06-21 | 2020-12-24 | Constellation Pharmaceuticals, Inc. | Methods of treating myeloproliferative disorders |
| US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| WO2021050992A1 (en) | 2019-09-11 | 2021-03-18 | Vincere Biosciences, Inc. | Usp30 inhibitors and uses thereof |
| WO2021050964A1 (en) | 2019-09-13 | 2021-03-18 | Nimbus Saturn, Inc. | Hpk1 antagonists and uses thereof |
| JP2022552324A (en) | 2019-10-14 | 2022-12-15 | インサイト・コーポレイション | Bicyclic heterocycles as FGFR inhibitors |
| WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| US11306062B2 (en) | 2019-10-29 | 2022-04-19 | Johnson Matthey Public Limited | Forms of fedratinib dihydrochloride |
| BR112022008287A2 (en) | 2019-11-01 | 2022-07-26 | Navitor Pharm Inc | TREATMENT METHODS USING AN MTORC1 MODULATOR |
| EP4069695A1 (en) | 2019-12-04 | 2022-10-12 | Incyte Corporation | Derivatives of an fgfr inhibitor |
| CA3163875A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
| CA3163680A1 (en) | 2019-12-05 | 2021-06-10 | David John O'neill | Rapamycin analogs and uses thereof |
| WO2021127283A2 (en) | 2019-12-17 | 2021-06-24 | Kymera Therapeutics, Inc. | Irak degraders and uses thereof |
| JP2023509366A (en) | 2019-12-17 | 2023-03-08 | カイメラ セラピューティクス， インコーポレイテッド | IRAK dissolving agents and their uses |
| JP2023509394A (en) | 2019-12-23 | 2023-03-08 | カイメラ セラピューティクス， インコーポレイテッド | SMARCA decomposing agents and their use |
| CN111423419B (en) * | 2020-01-17 | 2021-12-17 | 温州医科大学 | Small molecular compound cyy-260 and application thereof in preparation of antitumor drugs |
| AR121506A1 (en) | 2020-03-03 | 2022-06-08 | Pic Therapeutics Inc | EIF4E INHIBITORS AND THEIR USES |
| IL296451A (en) | 2020-03-19 | 2022-11-01 | Kymera Therapeutics Inc | Mdm2 degraders and uses thereof |
| US11833155B2 (en) | 2020-06-03 | 2023-12-05 | Incyte Corporation | Combination therapy for treatment of myeloproliferative neoplasms |
| TW202210483A (en) | 2020-06-03 | 2022-03-16 | 美商凱麥拉醫療公司 | Crystalline forms of irak degraders |
| CN113754591B (en) * | 2020-06-05 | 2024-01-05 | 山东大学 | HDAC, JAK and BET three-target inhibitor and preparation method and application thereof |
| EP3944859A1 (en) | 2020-07-30 | 2022-02-02 | Assistance Publique Hôpitaux de Paris | Method for treating immune toxicities induced by immune checkpoint inhibitors |
| AU2021327130A1 (en) | 2020-08-17 | 2023-03-02 | Bicycletx Limited | Bicycle conjugates specific for Nectin-4 and uses thereof |
| CN112225703B (en) * | 2020-09-28 | 2022-03-11 | 广州智睿医药科技有限公司 | Medicine for treating or preventing diseases related to LRRK2 kinase or abnormal LRRK2 mutant kinase activity |
| US20230391775A1 (en) * | 2020-10-29 | 2023-12-07 | Suzhou Yabao Pharmaceutical R&D Co., Ltd. | Substituted diarylamine compound, pharmaceutical composition thereof, preparation method therefor, and use thereof |
| TWI750905B (en) * | 2020-11-19 | 2021-12-21 | 財團法人國家衛生研究院 | Thiazole compounds as protein kinase inhibitors |
| WO2022120353A1 (en) | 2020-12-02 | 2022-06-09 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
| AU2021392040A1 (en) | 2020-12-02 | 2023-06-29 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
| TW202237119A (en) | 2020-12-10 | 2022-10-01 | 美商住友製藥腫瘤公司 | Alk-5 inhibitors and uses thereof |
| US20240058336A1 (en) | 2020-12-16 | 2024-02-22 | Impact Biomedicines, Inc. | Dosing of fedratinib |
| WO2022143628A1 (en) * | 2020-12-29 | 2022-07-07 | 上海岸阔医药科技有限公司 | Method for preventing or treating disease or condition associated with antitumor agent |
| CN112778282B (en) * | 2021-01-06 | 2022-07-22 | 温州医科大学 | Pyrimidine micromolecule compound and application thereof |
| EP4288427A1 (en) | 2021-02-02 | 2023-12-13 | Liminal Biosciences Limited | Gpr84 antagonists and uses thereof |
| WO2022167445A1 (en) | 2021-02-02 | 2022-08-11 | Liminal Biosciences Limited | Gpr84 antagonists and uses thereof |
| TW202245789A (en) | 2021-02-15 | 2022-12-01 | 美商凱麥拉醫療公司 | Irak4 degraders and uses thereof |
| JP2024507938A (en) | 2021-02-25 | 2024-02-21 | インパクト バイオメディシンズ インコーポレイテッド | Use of BET inhibitors as a treatment for myelofibrosis |
| JP2024509192A (en) | 2021-03-05 | 2024-02-29 | ニンバス サターン， インコーポレイテッド | HPK1 antagonists and their uses |
| KR102585194B1 (en) * | 2021-03-26 | 2023-10-10 | 주식회사 스탠다임 | Novel phenylaminopyrimidine compounds with inhibitory activity against LRRK2 and their uses |
| AU2022243600A1 (en) * | 2021-03-26 | 2023-10-12 | Sumitomo Pharma Oncology, Inc. | Alk-5 inhibitors and uses thereof |
| KR20230172548A (en) | 2021-04-16 | 2023-12-22 | 이케나 온콜로지, 인코포레이티드 | MEK inhibitors and uses thereof |
| AR126102A1 (en) | 2021-06-09 | 2023-09-13 | Incyte Corp | TRICYCLIC HETEROCYCLES AS FGFR INHIBITORS |
| WO2023028238A1 (en) | 2021-08-25 | 2023-03-02 | PIC Therapeutics, Inc. | Eif4e inhibitors and uses thereof |
| IL310924A (en) | 2021-08-25 | 2024-04-01 | Pic Therapeutics Inc | Eif4e inhibitors and uses thereof |
| WO2023044297A1 (en) | 2021-09-14 | 2023-03-23 | Impact Biomedicines, Inc. | Fedratinib for treating myeloproliferative disorders |
| WO2023043630A1 (en) * | 2021-09-16 | 2023-03-23 | Lomond Therapeutics, Inc. | Compounds having n-arylpyrimidin-2-amine derivatives as therapeutic agents |
| WO2023114984A1 (en) | 2021-12-17 | 2023-06-22 | Ikena Oncology, Inc. | Tead inhibitors and uses thereof |
| EP4238564A1 (en) * | 2022-03-02 | 2023-09-06 | Bash Biotech Inc | New treatments of renal cell carcinoma |
| WO2023173057A1 (en) | 2022-03-10 | 2023-09-14 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
| WO2023173053A1 (en) | 2022-03-10 | 2023-09-14 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
| WO2023211889A1 (en) | 2022-04-25 | 2023-11-02 | Ikena Oncology, Inc. | Polymorphic compounds and uses thereof |
| WO2023230205A1 (en) | 2022-05-25 | 2023-11-30 | Ikena Oncology, Inc. | Mek inhibitors and uses thereof |
| WO2024028365A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Substituted pyridone gpr84 antagonists and uses thereof |
| WO2024028364A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Aryl-triazolyl and related gpr84 antagonists and uses thereof |
| WO2024028363A1 (en) | 2022-08-02 | 2024-02-08 | Liminal Biosciences Limited | Heteroaryl carboxamide and related gpr84 antagonists and uses thereof |
Family Cites Families (151)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2A (en) * | 1826-12-15 | 1836-07-29 | mode of manufacturing wool or other fibrous materials | |
| US2003199A (en) | 1930-05-31 | 1935-05-28 | Johnson Frank James | Automatic coal stoker |
| US2003149A (en) | 1931-05-22 | 1935-05-28 | Autographic Register Co | Manifolding |
| US2003065A (en) | 1931-06-20 | 1935-05-28 | John R Ditmars | Composition for coating sheets, fibrous stocks, and the like |
| US2004102A (en) | 1932-02-24 | 1935-06-11 | Daniel A Dickey | Hollow steel propeller construction |
| US2004138A (en) | 1932-11-30 | 1935-06-11 | Byers A M Co | Method of making wrought iron pipe |
| US2002165A (en) | 1933-07-08 | 1935-05-21 | Charles A Winslow | Air cleaner |
| US2003187A (en) | 1933-10-02 | 1935-05-28 | Frederick H Shaw | Automobile radio device |
| US2003166A (en) | 1933-10-26 | 1935-05-28 | Zancan Ottavio | Front drive for motor cars |
| US2001051A (en) | 1933-12-01 | 1935-05-14 | Angelina Mariani | Tamperproof meter box with cutout control and fuse drawer for electric meters |
| US2004092A (en) | 1933-12-15 | 1935-06-11 | John L Chaney | Device for indicating the temperature of liquids |
| US2003060A (en) | 1934-04-02 | 1935-05-28 | Ernest L Heckert | Thermostatic controlling device |
| US2667486A (en) | 1951-05-24 | 1954-01-26 | Research Corp | 2,4-diamino pteridine and derivatives |
| IE38778B1 (en) | 1973-02-02 | 1978-05-24 | Ciba Geigy | New 1,2,4-benzotriazine derivatives |
| AU535258B2 (en) | 1979-08-31 | 1984-03-08 | Ici Australia Limited | Benzotriazines |
| DE3205638A1 (en) | 1982-02-17 | 1983-08-25 | Hoechst Ag, 6230 Frankfurt | Trisubstituted pyrimidine-5-carboxylic acids and their derivatives, processes for their preparation, and their use as pesticides |
| US4490289A (en) | 1982-09-16 | 1984-12-25 | Hoffmann-La Roche Inc. | Homogeneous human interleukin 2 |
| US5624925A (en) | 1986-09-25 | 1997-04-29 | Sri International | 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents |
| JP2598100B2 (en) | 1988-08-31 | 1997-04-09 | キヤノン株式会社 | Electrophotographic photoreceptor |
| US5214059A (en) | 1989-07-03 | 1993-05-25 | Hoechst-Roussel Pharmaceuticals Incorporated | 2-(aminoaryl) indoles and indolines as topical antiinflammatory agents for the treatment of skin disorders |
| US5776502A (en) | 1989-07-18 | 1998-07-07 | Oncogene Science, Inc. | Methods of transcriptionally modulating gene expression |
| US5665543A (en) | 1989-07-18 | 1997-09-09 | Oncogene Science, Inc. | Method of discovering chemicals capable of functioning as gene expression modulators |
| GB9003553D0 (en) | 1990-02-16 | 1990-04-11 | Ici Plc | Herbicidal compositions |
| MY107955A (en) | 1990-07-27 | 1996-07-15 | Ici Plc | Fungicides. |
| GB9016800D0 (en) | 1990-07-31 | 1990-09-12 | Shell Int Research | Tetrahydropyrimidine derivatives |
| DE4025891A1 (en) | 1990-08-16 | 1992-02-20 | Bayer Ag | PYRIMIDYL-SUBSTITUTED ACRYLIC ACID ESTERS |
| PL166991B1 (en) * | 1991-05-03 | 1995-07-31 | Raision Margariini Oy | Substance for lowering cholesterol level in blood serum and method of obtaining same |
| JPH05345780A (en) | 1991-12-24 | 1993-12-27 | Kumiai Chem Ind Co Ltd | Pyrimidine or triazine derivative and herbicide |
| HUT63941A (en) | 1992-05-15 | 1993-11-29 | Hoechst Ag | Process for producing 4-alkyl-substituted pyrimidine-5-carboxanilide derivatives, and fungicidal compositions comprising same |
| DE4338704A1 (en) | 1993-11-12 | 1995-05-18 | Hoechst Ag | Stabilized oligonucleotides and their use |
| US5530000A (en) | 1993-12-22 | 1996-06-25 | Ortho Pharmaceutical Corporation | Substituted pyrimidinylaminothiazole derivatives useful as platelet aggreggation inhibitors |
| GB9506466D0 (en) | 1994-08-26 | 1995-05-17 | Prolifix Ltd | Cell cycle regulated repressor and dna element |
| US5597826A (en) | 1994-09-14 | 1997-01-28 | Pfizer Inc. | Compositions containing sertraline and a 5-HT1D receptor agonist or antagonist |
| DE19502912A1 (en) | 1995-01-31 | 1996-08-01 | Hoechst Ag | G-Cap Stabilized Oligonucleotides |
| US6326487B1 (en) | 1995-06-05 | 2001-12-04 | Aventis Pharma Deutschland Gmbh | 3 modified oligonucleotide derivatives |
| GB9523675D0 (en) | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
| AU1977997A (en) | 1996-02-23 | 1997-09-10 | Eli Lilly And Company | Non-peptidyl vasopressin v1a antagonists |
| DE59707681D1 (en) | 1996-10-28 | 2002-08-14 | Rolic Ag Zug | Crosslinkable, photoactive silane derivatives |
| EP0968284B1 (en) | 1996-11-20 | 2006-12-13 | Introgen Therapeutics, Inc. | An improved method for the production and purification of adenoviral vectors |
| JP3734903B2 (en) | 1996-11-21 | 2006-01-11 | 富士写真フイルム株式会社 | Development processing method |
| JP3720931B2 (en) | 1996-11-26 | 2005-11-30 | 富士写真フイルム株式会社 | Processing method of silver halide photographic light-sensitive material |
| US5935383A (en) | 1996-12-04 | 1999-08-10 | Kimberly-Clark Worldwide, Inc. | Method for improved wet strength paper |
| DE59807348D1 (en) | 1997-02-05 | 2003-04-10 | Rolic Ag Zug | Photocrosslinkable silane derivatives |
| GB9705361D0 (en) * | 1997-03-14 | 1997-04-30 | Celltech Therapeutics Ltd | Chemical compounds |
| US6070126A (en) | 1997-06-13 | 2000-05-30 | William J. Kokolus | Immunobiologically-active linear peptides and method of identification |
| US6635626B1 (en) | 1997-08-25 | 2003-10-21 | Bristol-Myers Squibb Co. | Imidazoquinoxaline protein tyrosine kinase inhibitors |
| ES2308821T3 (en) | 1997-12-15 | 2008-12-01 | Astellas Pharma Inc. | NEW DERIVATIVES OF PIRIMIDIN-5-CARBOXAMIDA. |
| BRPI9909191B8 (en) | 1998-03-27 | 2021-07-06 | Janssen Pharmaceutica Nv | hiv inhibitor pyrimidine derivatives, their use and pharmaceutical composition comprising them |
| US6685938B1 (en) | 1998-05-29 | 2004-02-03 | The Scripps Research Institute | Methods and compositions useful for modulation of angiogenesis and vascular permeability using SRC or Yes tyrosine kinases |
| US6136971A (en) | 1998-07-17 | 2000-10-24 | Roche Colorado Corporation | Preparation of sulfonamides |
| US6378526B1 (en) | 1998-08-03 | 2002-04-30 | Insite Vision, Incorporated | Methods of ophthalmic administration |
| AU5438299A (en) * | 1998-08-29 | 2000-03-21 | Astrazeneca Ab | Pyrimidine compounds |
| US6297258B1 (en) | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| US6288082B1 (en) | 1998-09-29 | 2001-09-11 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| GB9828511D0 (en) * | 1998-12-24 | 1999-02-17 | Zeneca Ltd | Chemical compounds |
| BRPI0009721B1 (en) * | 1999-04-15 | 2018-11-21 | Bristol-Myers Squibb Holdings Ireland | cyclic protein tyrosine kinase inhibitors |
| EP1193255A4 (en) | 1999-07-01 | 2002-08-07 | Ajinomoto Kk | Heterocyclic compounds and medicinal use thereof |
| WO2001007032A1 (en) | 1999-07-23 | 2001-02-01 | Shionogi & Co., Ltd. | Th2 differentiation inhibitors |
| US6093838A (en) | 1999-08-16 | 2000-07-25 | Allergan Sales, Inc. | Amines substituted with a dihydro-benzofuranyl or with a dihydro-isobenzofuranyl group, an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity |
| US6127382A (en) | 1999-08-16 | 2000-10-03 | Allergan Sales, Inc. | Amines substituted with a tetrahydroquinolinyl group an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity |
| JP2001089412A (en) | 1999-09-22 | 2001-04-03 | Otsuka Pharmaceut Co Ltd | Benzene derivative or its pharmaceutically acceptable salt |
| US6506769B2 (en) | 1999-10-06 | 2003-01-14 | Boehringer Ingelheim Pharmaceuticals, Inc. | Heterocyclic compounds useful as inhibitors of tyrosine kinases |
| US7087597B1 (en) * | 1999-10-12 | 2006-08-08 | Takeda Pharmaceutical Company Limited | Pyrimidine 5-carboxamide compounds, process for producing the same and use thereof |
| GB9924092D0 (en) * | 1999-10-13 | 1999-12-15 | Zeneca Ltd | Pyrimidine derivatives |
| US6638929B2 (en) | 1999-12-29 | 2003-10-28 | Wyeth | Tricyclic protein kinase inhibitors |
| US6153752A (en) | 2000-01-28 | 2000-11-28 | Creanova, Inc. | Process for preparing heterocycles |
| US20020165244A1 (en) | 2000-01-31 | 2002-11-07 | Yuhong Zhou | Mucin synthesis inhibitors |
| CN1429222A (en) | 2000-02-17 | 2003-07-09 | 安姆根有限公司 | Kinase inhibitors |
| WO2001064646A2 (en) | 2000-03-01 | 2001-09-07 | Tularik Inc. | Hydrazones and analogs as cholesterol lowering agents |
| GB0004890D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| GB0004888D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| GB0004887D0 (en) * | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| JP2001247411A (en) | 2000-03-09 | 2001-09-11 | Tomono Agrica Co Ltd | Pest-controlling agent |
| US6608048B2 (en) | 2000-03-28 | 2003-08-19 | Wyeth Holdings | Tricyclic protein kinase inhibitors |
| AU2001244614A1 (en) | 2000-04-04 | 2001-10-15 | Shionogi & Co., Ltd. | Oily compositions containing highly fat-soluble drugs |
| FR2808163B1 (en) * | 2000-04-19 | 2002-11-08 | Celes | TRANSVERSE FLOW INDUCTION HEATING DEVICE WITH MAGNETIC CIRCUIT OF VARIABLE WIDTH |
| US6471968B1 (en) | 2000-05-12 | 2002-10-29 | Regents Of The University Of Michigan | Multifunctional nanodevice platform |
| DE10024622A1 (en) | 2000-05-18 | 2001-11-22 | Piesteritz Stickstoff | New N-(2-pyrimidinyl)-(thio)phosphoric acid triamide compounds are urease inhibitors useful for preventing hydrolysis of urea fertilizers or for reducing release of ammonia in animal stalls |
| US6875483B2 (en) | 2000-07-06 | 2005-04-05 | Fuji Photo Film Co., Ltd. | Liquid crystal composition comprising liquid crystal molecules and alignment promoter |
| ATE385498T1 (en) | 2000-08-11 | 2008-02-15 | Boehringer Ingelheim Pharma | HETEROCYCLIC COMPOUNDS AS INHIBITORS OF TYROSINE KINASES |
| JP2002221770A (en) | 2001-01-24 | 2002-08-09 | Fuji Photo Film Co Ltd | Silver halide photographic sensitive material and method of processing the same |
| WO2002083667A2 (en) * | 2001-04-13 | 2002-10-24 | Vertex Pharmaceuticals Incorporated | Inhibitors of c-jun n-terminal kinases (jnk) and other protein kinases |
| NZ528961A (en) * | 2001-04-20 | 2005-04-29 | Bayer Cropscience Ag | Novel insecticidal azoles |
| AU2002314252A1 (en) | 2001-05-28 | 2002-12-09 | Aventis Pharma S.A. | Chemical derivatives and the use thereof as an anti-telomerase agent |
| PL367130A1 (en) | 2001-05-29 | 2005-02-21 | Schering Aktiengesellschaft | Cdk inhibiting pyrimidines, production thereof and their use as medicaments |
| ES2271283T3 (en) | 2001-07-03 | 2007-04-16 | Vertex Pharmaceuticals Incorporated | ISOXAZOLIL-PIRIMIDINAS AS INHIBITORS OF THE PROTEINAS QUINASAS SRC AND LCK. |
| EP1453516A2 (en) * | 2001-10-17 | 2004-09-08 | Boehringer Ingelheim Pharma GmbH & Co.KG | Novel tri-substituted pyrimidines, method for production and use thereof as medicament |
| US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
| US20030166932A1 (en) | 2002-01-04 | 2003-09-04 | Beard Richard L. | Amines substituted with a dihydronaphthalenyl, chromenyl, or thiochromenyl group, an aryl or heteroaryl group and an alkyl group, having retinoid-like biological activity |
| TWI329105B (en) * | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| US7338959B2 (en) | 2002-03-01 | 2008-03-04 | Smithkline Beecham Corporation | Diamino-pyrimidines and their use as angiogenesis inhibitors |
| GB0206215D0 (en) * | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
| WO2004005283A1 (en) | 2002-07-09 | 2004-01-15 | Vertex Pharmaceuticals Incorporated | Imidazoles, oxazoles and thiazoles with protein kinase inhibiting activities |
| ATE451104T1 (en) * | 2002-07-29 | 2009-12-15 | Rigel Pharmaceuticals Inc | METHOD FOR TREATING OR PREVENTING AUTOIMMUNE DISEASES USING 2,4-PYRIMIDINEDIAMINE COMPOUNDS |
| CA2494695C (en) | 2002-08-02 | 2011-04-05 | Ab Science | 2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors |
| BR0313397A (en) | 2002-08-14 | 2005-06-28 | Vertex Pharmaceuticals Incorpo | Protein kinase inhibitors and uses of these |
| UY27939A1 (en) | 2002-08-21 | 2004-03-31 | Glaxo Group Ltd | COMPOUNDS |
| DE10240262A1 (en) | 2002-08-31 | 2004-03-11 | Clariant Gmbh | Production of aryllithium-electrophile reaction products of interest for the pharmaceutical and agrochemical industries comprises using an organolithium compound prepared by reacting an aryl halide with lithium |
| DE10240261A1 (en) | 2002-08-31 | 2004-03-11 | Clariant Gmbh | Production of aryllithium-electrophile reaction products of interest for the pharmaceutical and agrochemical industries comprises using an organolithium compound prepared by reacting an aryl halide with lithium |
| KR20050056227A (en) | 2002-10-03 | 2005-06-14 | 탈자진 인코포레이티드 | Vasculostatic agents and methods of use thereof |
| US20050282814A1 (en) | 2002-10-03 | 2005-12-22 | Targegen, Inc. | Vasculostatic agents and methods of use thereof |
| AU2003286711A1 (en) | 2002-10-25 | 2004-05-13 | Vertex Pharmaceuticals Incorporated | Indazolinone compositions useful as kinase inhibitors |
| US7452911B2 (en) | 2002-10-31 | 2008-11-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds |
| DE10250708A1 (en) | 2002-10-31 | 2004-05-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New alkyne compounds having MCH antagonist activity and medicaments containing these compounds |
| EP1562938B1 (en) | 2002-11-04 | 2007-08-29 | Vertex Pharmaceuticals Incorporated | Heteroaryl-pyrimidine derivatives as jak inhibitors |
| US7112676B2 (en) * | 2002-11-04 | 2006-09-26 | Hoffmann-La Roche Inc. | Pyrimido compounds having antiproliferative activity |
| US20050101576A1 (en) * | 2003-11-06 | 2005-05-12 | Novacea, Inc. | Methods of using vitamin D compounds in the treatment of myelodysplastic syndromes |
| AU2003280188A1 (en) | 2002-12-06 | 2004-06-30 | Warner-Lambert Company Llc | Benzoxazin-3-ones and derivatives thereof as inhibitors of pi3k |
| WO2004054186A1 (en) | 2002-12-12 | 2004-06-24 | Fujitsu Limited | Data relay apparatus, associative memory device, and associative memory device utilization information search method |
| JP2006514050A (en) | 2002-12-20 | 2006-04-27 | ファルマシア・コーポレーション | R isomers of β-amino acid compounds as integrin receptor antagonist derivatives |
| BR0317600A (en) | 2002-12-20 | 2005-11-29 | Pharmacia Corp | heteroarylalkanoic acids as derivatives of integrin receptor antagonists |
| ATE412657T1 (en) | 2002-12-24 | 2008-11-15 | Astrazeneca Ab | THERAPEUTIC QUINAZOLINE DERIVATIVES |
| CL2004000192A1 (en) | 2003-02-07 | 2005-03-18 | Janssen Pharmaceutica Nv | USE OF COMPOUNDS DERIVED FROM 2-AMINOPIRIMIDINE TO PREPARE A MEDICINAL PRODUCT FOR THE PREVENTION OF HIV INFECTION SEXUAL RELATIONS OR AN INTIMATE COUPLE CONTACT. |
| AP2005003365A0 (en) | 2003-02-07 | 2005-09-30 | Janssen Pharmaceutica Nv | Hiv inhibiting 1, 2, 4-triazines. |
| CL2004000306A1 (en) | 2003-02-20 | 2005-04-08 | Tibotec Pharm Ltd | COMPOUNDS DERIVED FROM PYRIMIDINE REPLACED WITH INDANO; PROCESS FOR PREPARATION; PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS IT; PHARMACEUTICAL COMBINATION; AND ITS USE FOR THE TREATMENT OR PROFILAXIS OF AN INFECTIOUS DISEASE. |
| GB0305929D0 (en) | 2003-03-14 | 2003-04-23 | Novartis Ag | Organic compounds |
| EP1623269B2 (en) | 2003-04-24 | 2022-08-31 | CooperVision International Limited | Hydrogel contact lenses and package systems and production methods for same |
| WO2005016893A2 (en) * | 2003-07-30 | 2005-02-24 | Rigel Pharmaceuticals, Inc. | 2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases |
| MXPA06001759A (en) * | 2003-08-15 | 2006-05-12 | Novartis Ag | 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders. |
| GB0321710D0 (en) | 2003-09-16 | 2003-10-15 | Novartis Ag | Organic compounds |
| MXPA06003054A (en) * | 2003-09-18 | 2006-05-31 | Novartis Ag | 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders. |
| KR20070011458A (en) * | 2004-04-08 | 2007-01-24 | 탈자진 인코포레이티드 | Benzotriazine inhibitors of kinases |
| MX2007002208A (en) | 2004-08-25 | 2007-05-08 | Targegen Inc | Heterocyclic compounds and methods of use. |
| US7210697B2 (en) | 2004-12-16 | 2007-05-01 | Tricam International, Inc. | Convertible handle |
| WO2006074057A2 (en) * | 2004-12-30 | 2006-07-13 | Exelixis, Inc. | Pyrimidine derivatives as kinase modulators and method of use |
| WO2006101977A2 (en) * | 2005-03-16 | 2006-09-28 | Targegen, Inc. | Pyrimidine compounds and methods of use |
| US7389455B2 (en) * | 2005-05-16 | 2008-06-17 | Texas Instruments Incorporated | Register file initialization to prevent unknown outputs during test |
| US20070032493A1 (en) | 2005-05-26 | 2007-02-08 | Synta Pharmaceuticals Corp. | Method for treating B cell regulated autoimmune disorders |
| WO2006133426A2 (en) | 2005-06-08 | 2006-12-14 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| MX2007008848A (en) | 2005-06-08 | 2008-04-16 | Targegen Inc | Methods and compositions for the treatment of ocular disorders. |
| KR100848205B1 (en) | 2005-06-20 | 2008-07-24 | 주식회사 동부하이텍 | New substituted 1,3-thiazole derivatives or pharmaceutically acceptable salts thereof having immunosuppression and inflammation inhibitory activity, intermediate compounds or pharmaceutically acceptable salts thereof, a process for the preparation thereof, and pharmaceutical composition comprising the same |
| WO2007008541A2 (en) * | 2005-07-08 | 2007-01-18 | Kalypsys, Inc. | Cellular cholesterol absorption modifiers |
| EP2270014A1 (en) * | 2005-09-22 | 2011-01-05 | Incyte Corporation | Azepine inhibitors of janus kinases |
| US20070072682A1 (en) | 2005-09-29 | 2007-03-29 | Crawford James T Iii | Head to head electronic poker game assembly and method of operation |
| RU2597364C2 (en) | 2005-11-01 | 2016-09-10 | Таргеджен, Инк. | Bi-aryl-meta-pyrimidine kinase inhibitors |
| US8133900B2 (en) | 2005-11-01 | 2012-03-13 | Targegen, Inc. | Use of bi-aryl meta-pyrimidine inhibitors of kinases |
| US20070149508A1 (en) | 2005-11-02 | 2007-06-28 | Targegen, Inc. | Six membered heteroaromatic inhibitors targeting resistant kinase mutations |
| JP2009519218A (en) | 2005-11-03 | 2009-05-14 | エスジーエックス ファーマシューティカルズ、インコーポレイテッド | Pyrimidinyl-thiophene kinase modulator |
| US8143255B2 (en) | 2005-11-16 | 2012-03-27 | S*Bio Pte Ltd. | Heteroalkyl linked pyrimidine derivatives |
| WO2007070514A1 (en) * | 2005-12-13 | 2007-06-21 | Incyte Corporation | Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as janus kinase inhibitors |
| CA2642229C (en) * | 2006-02-24 | 2015-05-12 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| US7691858B2 (en) | 2006-04-25 | 2010-04-06 | Targegen, Inc. | Kinase inhibitors and methods of use thereof |
| WO2008008234A1 (en) * | 2006-07-07 | 2008-01-17 | Targegen, Inc. | 2-amino-5-substituted pyrimidine inhibitors |
| US20100010025A1 (en) | 2006-07-21 | 2010-01-14 | Norvartis Ag | Pyrimidine Derivatives |
| US20080021013A1 (en) * | 2006-07-21 | 2008-01-24 | Cephalon, Inc. | JAK inhibitors for treatment of myeloproliferative disorders |
| RS58449B1 (en) | 2007-06-13 | 2019-04-30 | Incyte Holdings Corp | Use of salts of the janus kinase inhibitor (r)-3-(4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-1h- pyrazol-1-yl)-3- cyclopentylpropanenitrile |
| WO2009046416A1 (en) | 2007-10-05 | 2009-04-09 | Targegen Inc. | Anilinopyrimidines as jak kinase inhibitors |
| CA2730847A1 (en) * | 2008-07-14 | 2010-01-21 | Otonomy, Inc. | Controlled-release apoptosis modulating compositions and methods for the treatment of otic disorders |
| RU2011108563A (en) | 2008-08-05 | 2012-09-10 | Таргеджен, Инк. (US) | THALASSEMIA TREATMENT METHODS |
| DK2376500T3 (en) | 2008-12-11 | 2015-05-04 | Cti Biopharma Corp | 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaenmaleatsalt |
| US20100278921A1 (en) | 2009-04-30 | 2010-11-04 | Fischer Cristina M | Solid oral formulation of abt-263 |
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